Inhibitors of hepatitis C virus polymerase

ABSTRACT

The present invention provides, among other things, compounds represented by the general Formula I: and pharmaceutically acceptable salts thereof, wherein X, Y, R 2 , and R 3  are as defined in classes and subclasses herein and compositions (e.g., pharmaceutical compositions) comprising such compounds, which compounds are useful as inhibitors of hepatitis C virus polymerase, and thus are useful, for example, as medicaments for the treatment of HCV infection.

The invention provides compounds, compositions, and methods for thetreatment of hepatitis C virus infection in humans.

BACKGROUND

Hepatitis C virus (HCV) is an enveloped, positive-sense, single-strandedRNA virus, of the genus Hepacivirus, belonging to the familyFlaviviridae. Infection by HCV is a leading cause of liver disease andcirrhosis in humans. Transmission occurs primarily by way ofpercutaneous exposure to infected blood, typically involving use ofinjected drugs or injury with objects contaminated with blood, but isalso associated with sexual contact with infected partners. Thanks toviral testing, risk of transmission by blood transfusion or bytransplant is extremely low. Infection is often asymptomatic, orsymptoms are mild, and about 15-20% of infected persons are able toclear the virus without treatment. However, infection in the remaining80-85% of infected persons develops into persistent infection, which maybe life-long, causing liver disease, which can lead to cirrhosis andhepatocellular carcinoma. HCV infection is the most common chronicblood-borne disease in the United States, affecting about 4 millionpeople and causing about 12,000 deaths per year. “Evaluation of AcuteHepatitis C Infection Surveillance United States, 2008,” MMWR, Nov. 5,2010, 59(43). Approximately 170 million persons around the world havechronic hepatitis C infection. Chen et al., Int J Med Sci, 2006,3(2):47-52. Personal consequences of HCV infection include decreasedlife expectancy, chronic debilitating liver disease and possibly livercancer, and risk of infection of sexual partners and health careworkers. Economic consequences of chronic HCV infection in the UnitedStates are exceedingly large. Direct medical costs have been estimatedat $10.7 billion per year for the 10-year period 2010-2019, withsocietal costs projected to be $54.2 billion, and the cost of morbidityfrom disability projected to be $21.3 billion. Id.

The hepatitis C virus has been intensively studied, and much is knownabout its genetics and biology. For an overview of this subject, seeTan, Ed., Hepatitis C Viruses: Genomes and Molecular Biology, HorizonBioscience, Norfolk, UK (2006). HCV has a simple genome that resides ina single open reading frame of about 9.6 kb. The genome is translated inthe infected cell to yield a single polyprotein consisting of about 3000amino acids, which is then proteolytically processed by host and viralenzymes to produce at least 10 structural and non-structural (NS)proteins. The virus is diversified in infected humans into 16 differentantigenically and/or genetically identifiable subtypes or genotypes,some of which are further subdivided into subtypes.

HCV rapidly mutates as it replicates, and is believed to exist as aviral quasispecies, meaning that it mutates rapidly as it replicates togenerate many competing genetic varieties of the virus having comparableevolutionary fitness. This intrinsic generation of many varieties in asingle infected person makes it very difficult to isolate a singlevariety for development of a vaccine, and is believed to be associatedwith the difficulty in developing a vaccine, development of resistanceof the virus to specific pharmaceuticals, and persistence of the virusin the host. It is possible that the virus able to develop intoimmunologically distinct quasispecies under the pressure of the immuneresponse of the host, thereby allowing it to survive and persist.

Another factor making it difficult to develop treatments for HCVinfection is the narrow range of hosts and a notoriously difficultproblem of propagating the virus in cell culture. Most research has beendone using pseudoparticle systems. Pseudoparticles consist primarily ofnucleocapsids surrounded by a lipid envelope and contain HCVglycoprotein complexes. These pseudoparticles have been used toelucidate the early stages of the viral replication cycle and receptorbinding, and to study neutralizing antibodies. Notwithstanding,pseudoparticles have a significant limitation in that they cannotrecapitulate the full replication cycle. Other systems described forinvestigation of HCV include culture of subgenomic RNAs in Huh-7 cells,and culture in primary human hepatocytes, and surrogate models such asthe bovine viral diarrhea virus (BVDV).

Significant research has also been done in synthetic RNA replicons,which self-amplify in human hepatoma cells and recapitulate much, butnot all, of the HCV replication cycle. Heretofore, such replicons havebeen subgenomic, and have also been unable to yield infectious viralparticles. Moreover, such a replicon system appears to function onlyusing the 1b genotype of HCV (HCV1b). More recently, HCV cell culturehas become possible through the isolation of the JFH-1 clone (HCV 2a).While its uniqueness remains incompletely understood, JFH-1 replicatesto high levels in Huh-7 (hepatocellular carcinoma) cells and other celltypes in culture, and produces infectious particles. Serial passage ofJFH-1 has caused it to become genetically conditioned to cell cultureconditions and it may no longer be representative of clinical isolatesof the virus, but the viral particles are apparently functional virions,insofar as they are infectious in culture and in inoculated animalsbearing human liver xenografts. Apparently, the efficiency of JFH-1replication depends significantly upon the NS5B gene of the clone.Replacement with NS5B genes from other genotypes is difficult. Woerz etal., 2009, J Viral Hepat, 16(1):1-9. Other replicon systems have beendeveloped with various replication markers and for different HCVgenotypes, including HCV 1a and HCV 2a. See, Huang et al., “Hepatitis CVirus-related Assays,” Chapter 2 in Hepatitis C: Antiviral DrugDiscovery and Development, S-L Tan and Y He, eds., Caister AcademicPress (2011), at pp 56-57.

Currently there no treatment that is effective to cure HCV infection.Palliative treatments include reduction of circulating virus. This maybe accomplished through blood filtration, e.g., by double filtrationplasmapheresis, lectin affinity plasmapheresis, or a combination of thetwo methods, but this treatment requires repetitive application and maybest be used in conjunction with standard-of-care pharmaceuticaltreatment.

Approved pharmaceutical treatments include injection of interferon,typically pegylated versions including peginterferon alfa-2a (Pegasys®)or peginterferon alfa-2b (PegIntron®). Clinical use of pegylatedinterferon was approved by FDA in 2001. Ribavirin (e.g., Ribasphere®,Virazole®, Copegus®, Rebetol®), a guanosine analog that hasbroad-spectrum activity against viruses, is used to treat HCV infection,but appears not to be effective against HCV when used as a monotherapy.Current standard-of-care therapy includes administering peginterferon incombination with ribavirin. This regimen is limited because of sideeffects (e.g., flu-like symptoms, leukopenia, thrombocytopenia,depression, and anemia) and only moderate efficacy; success is dependentin part on the genotype predominating in the patient. See Ghany et al.,Hepatology, 2011, 54(4):1433-44.

Numerous alternative pharmaceutical approaches to treatment of HCVinfection are now in research and development. For example, recombinantand modified interferon molecules have also been the subject ofdevelopment programs, including, e.g., recombinant alfa interferon(BLX-883; Locteron®; Biolex/Octoplus) and albinterferon alfa 2b(Zalbin®; Human Genome Sciences).

The HCV protein NS3-4A, a serine protease, which is an enzyme essentialfor replication of the virus, has been the subject of intensivepharmaceutical research. A number of companies are seeking to developinhibitors of this enzyme. Some of the earlier molecules are telaprevir(Incivek®, VX-950; Vertex) and boceprevir (Victrelis®, SCH503034; Merck& Co.), each of which has been approved for use. These various moleculesmay be useful as single therapeutics, but some are also beinginvestigated in combination with interferon/ribavirin therapies and/orcompounds that may be effective against HCV via other mechanisms.However, viral resistance to individual protease inhibitors is believedto occur easily. Morrison and Haas, In Vivo, May 2009, 42-47.

The NS5B polymerase of HCV is also undergoing study. This protein is anRNA-dependent RNA polymerase (RdRp), which is essential for thesynthesis of viral RNA, and consequently, for the completion of theviral life cycle. An overview of the NS5B protein is available atChapter 10 of Tan, supra.

Many groups are currently working on developing inhibitors of the NS5Bpolymerase. Wang et al. (J Biol Chem 2003, 278(11), 9489-95) report thatcertain non-nucleoside molecules bind to an allosteric site on thepolymerase, interfering with a conformational change required foractivity. Biswal et al. (J Biol Chem, 2005, 280(18), 18202-10) reportcrystal structures indicating that the NS5B polymerase exhibits twoconformations, with a gross structure resembling the classical fingers,palm, and thumb domains of other polymerases. This paper also showcocrystal structures for two inhibitors bound to the polymerase, andoffers hypotheses on the mechanism of polymerase inhibition. Li et al.(J Med Chem, 2007, 50(17):3969-72) report on some dihydropyronecompounds that are said to be orally available allosteric inhibitors.See also Li et al., J Med Chem, 2009, 52:1255-58.

Inhibitors of NS5B may be classified broadly into three groups:nucleoside analogues (NI), non-nucleoside analogues (NNI), andpyrophosphate compounds (PPi). See, Powdrill et al., Viruses, 2010,2:2169-95 and Appleby et al., “Viral RNA Polymerase Inhibitors,” Chapter23 in Viral Genome Replication, Cameron et al., eds., SpringerScience+Business Media 2009.

Nucleoside analogue compounds (NI), which bind at the enzyme active siteand compete with natural nucleoside triphosphates, interfere with viralRNA synthesis. A number of these compounds have entered clinical trials.Nucleoside inhibitors include, for example, IDX184 (Idenix), RG7128(RO5024048; Pharmasset/Roche).

Non-nucleoside inhibitors, by contrast, appear to bind at allostericsites on NS5B—of which about 4 are known. Id. NNI compounds include, forexample, filibuvir (Pfizer), tegobuvir (GS 9190; Gilead), VX-222(Vertex), A-837093 (Abbott), ABT-072 (Abbott), ABT-333 (Abbott), andPF-868554 (Pfizer).

Also among the non-nucleoside inhibitors of NS5B are a series ofthiophene-2-carboxylic acids and derivatives thereof. See, e.g., Chan etal., Bioorg Med Chem Lett, 2004, 14, 793-96; International patentpublications WO 02/100846 A1, WO 02/100851 A2, WO 2004/052879 A2, WO2004/052885 A1, WO 2006/072347 A2, WO 2006/119646 A1, WO 2008/017688 A1,WO 2008/043791 A2, WO 2008/058393 A1, WO 2008/059042 A1, WO 2008/125599A1, and WO 2009/000818 A1. See also U.S. Pat. Nos. 6,881,741 B2,7,402,608 B2, and 7,569,600 B2. See also, Yang et al., Bioorg Med ChemLett 2010, 20, 4614-19, relating to some bioisosteres of such compounds.Other similar compounds are described, for example, in U.S. Pat. Nos.6,887,877 B2 and 6,936,629 B2.

Pyrophosphate compounds (PPi) mimic natural pyrophosphates releasedduring nucleotidyl transfer reactions.

Various NI and NNI compounds have shown safety or efficacy in clinicaltrials, but none has yet reached approval for use in treating humans.PPi compounds, by contrast, are generally in the investigational stage.

There remains a profound need for more effective pharmaceuticaltherapies, including medicaments that are useful as single agents or incombination with other active agents, for the treatment of hepatitis Cinfection in humans.

SUMMARY OF THE INVENTION

The present invention provides compounds represented by the generalFormula I:

and salts (e.g., pharmaceutically acceptable salts) thereof, wherein X,Y, R², R³, and R⁴ are as defined in classes and subclasses herein andcompositions (e.g., pharmaceutical compositions) comprising suchcompounds, which compounds are useful as inhibitors of hepatitis C viruspolymerase, and thus are useful, for example, as medicaments for thetreatment of HCV infection.

In certain other embodiments, the invention provides pharmaceuticalcompositions comprising a compound of the invention, wherein thecompound is present in an amount effective to inhibit HCV polymeraseactivity. In certain other embodiments, the invention providespharmaceutical compositions comprising an inventive compound andoptionally further comprising an additional therapeutic agent. In yetother embodiments, the additional therapeutic agent is an agent for thetreatment of HCV infection.

In yet another aspect, the present invention provides methods forinhibiting HCV polymerase activity in a subject or a biological sample,comprising administering to the subject, or contacting the biologicalsample with an effective inhibitory amount of a compound of theinvention. In still another aspect, the present invention providesmethods for treating any disorder constitutively associated with HCVinfection or replication or involving HCV polymerase activity,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of the invention.

DETAILED DESCRIPTION

In another aspect, the invention provides compounds according to FormulaI:

and salts and solvates thereof,wherein:

-   -   one of X and Y is —CH₂— and the other is —NR¹—;    -   R¹ is —C₅₋₆hydroxyalkyl, —S(O)₂—C₀₋₄alkyl-R^(O),        —C₀₋₄alkyl-R^(O), —C₀₋₃alkyl-C(O)—C₀₋₄alkyl-R^(O),        —C₀₋₃alkyl-C(O)O—C₀₋₄alkyl-R^(O);        -   wherein:            -   R^(M) and R^(N) are independently hydrogen, —C₁₋₄alkyl,                or R^(M) and R^(N) together with the atoms to which they                are attached can form a 4- to 6-membered ring; and            -   R^(O) is (a) a 5- to 7-membered cycloalkyl or                heterocycloalkyl group, substituted with a —C₁₋₃alkyl,                aryl, —O-aryl, or —NR^(M)R^(N) moiety, (b) a 7-membered                cycloalkyl or heterocycloalkyl group [optionally                substituted with a hydroxyl], or (c) a 6- to 10-membered                aryl or a 5- to 10-membered heteroaryl group, in each                case monocyclic or bicyclic, and substituted with one to                three moieties independently selected from —C₁₋₄alkyl,                halogen, —NR^(M)R^(N), —C₁₋₄haloalkyl, —C₁₋₄alkoxy,                —C₁₋₄hydroxyalkyl, cyano, —O-aryl, and aryl, provided                that at least one such substitution is —C₁₋₄alkoxy,                —C₁₋₄hydroxyalkyl, cyano, or —O-aryl;    -   R² is —C₁₋₅alkyl optionally substituted with 1-5 halogens,        —C₁₋₅alkoxy, —C₅₋₇cycloalkyl-C₀₋₃alkyl in which the alkyl is        optionally substituted with 1-3 halogens,        —C₁₋₄alkyl-C₃₋₅cycloalkyl, or phenyl optionally substituted with        1 or 2 halogens or —C₁₋₃alkyl groups optionally substituted with        1-3 halogens;    -   R³ is —R^(A)—R^(B) or halo;        -   wherein R^(A) is ethynyl or is a phenyl or pyridinyl moiety            optionally substituted with one or two Z, in which each Z is            independently halogen, —C₁₋₃alkyl, —C₁₋₃haloalkyl,            —C₁₋₃alkoxy, or cyano; and        -   wherein R^(B) is hydrogen, —C₁₋₆alkyl,            —C₀₋₃alkyl-NR^(M)R^(N), —NHC₁₋₃alkyl-R^(Q),            —N(R^(U))C(O)—R^(Q), —C(O)NR^(U)R^(Q), carboxyl,            —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₃alkyl-C₃₋₆cycloalkyl,            —C₁₋₄alkoxy, -methyl-(C₁₋₄alkoxy)₁₋₂,            —C₀₋₃alkyl-NR^(S)R^(T), —C₃₋₇cycloalkyl-C₀₋₃alkyl-R^(Q),            —C₀₋₄alkyl-R^(Q), —C₂₋₆alkynylR^(Q), or —C₂₋₄alkenyl-R^(Q);            -   wherein R^(Q) is a 5- to 9-membered monocyclic or                bicyclic aryl or heteroaryl or a 3- to 7-membered                cycloalkyl or heterocycloalkyl, optionally substituted                with one or two R^(Z), in which each R^(Z) is                independently —C₁₋₃alkyl, —C₁₋₃alkoxy, or —NR^(M)R^(N);            -   R^(S) and R^(T) are each independently hydrogen or                —C₁₋₄alkyl, or one of R^(S) and R^(T) is hydrogen and                the other is —C(O)-5- to 9-membered aryl or heteroaryl;                and            -   R^(U) is hydrogen or —C₁₋₄alkyl;    -   provided that, when R^(A) is phenyl, then R^(B) appears at the        para or meta position relative to the thiophene moiety; and    -   R⁴ is hydrogen, —C₁₋₄alkyl, —C₁₋₄alkyl-OC(O)O—C₁₋₄alkyl,        —C₁₋₄alkyl-OC(O)—C₁₋₄alkyl, —C₁₋₄alkyl-OC(O)O—C₃₋₆cycloalkyl,        5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl-, —C₀₋₃alkyl-C₅₋₆aryl, or        —C₁₋₄alkyl-NR^(V)R^(W); and        -   R^(V) and R^(W) are independently hydrogen or —C₁₋₄alkyl.

In another aspect, the invention provides compounds according to FormulaI:

and salts and solvates thereof,wherein:

-   -   one of X and Y is —CH₂— and the other is —NR¹—;    -   R¹ is hydrogen, —C₁₋₄alkyl, —C₁₋₆hydroxyalkyl, —C₁₋₄haloalkyl,        —C₁₋₄alkyl-O—C₁₋₄alkyl, —S(O)₂—C₀₋₄alkyl-R^(O),        —C₀₋₄alkyl-S(O)₂—C₁₋₄alkyl, —C₀₋₄alkyl-S(O)₂—NR^(M)R^(N),        —C₂₋₄alkyl-NR^(M)R^(N), —C₀₋₄alkyl-R^(O),        —C₀₋₃alkyl-C(O)C₁₋₄alkyl, —C₀₋₃alkyl-C(O)—C₁₋₄hydroxyalkyl,        —C₀₋₃alkyl-C(O)—C₀₋₄alkyl-R^(O), —C(O)O—C₁₋₄alkyl,        —C₀₋₃alkyl-C(O)O—C₀₋₄alkyl-R^(O), —C₀₋₄alkyl-C(O)OH, or        —C₀₋₃alkyl-C(O)—C₀₋₄alkyl-NR^(M)R^(N);        -   wherein:            -   R^(M) and R^(N) are independently hydrogen, —C₁₋₄alkyl,                or R^(M) and R^(N) together with the atoms to which they                are attached can form a 4- to 6-membered ring; and            -   R^(O) is a 5- to 7-membered cycloalkyl or                heterocycloalkyl group, optionally substituted with a                hydroxyl, —C₁₋₃alkyl, aryl, —O-aryl, or —NR^(M)R^(N)                moiety, or is a 6- to 10-membered aryl or a 5- to                10-membered heteroaryl, in each case monocyclic or                bicyclic, and optionally substituted with (a) one to                three moieties independently selected from —C₁₋₄alkyl,                halogen, —NR^(M)R^(N), —C₁₋₄haloalkyl, —C₁₋₄alkoxy,                —C₁₋₄hydroxyalkyl, cyano, —O-aryl, and aryl, or (b) a                6-membered aryl or 5-6 membered heteroaryl, optionally                substituted with one to three moieties independently                selected from —C₁₋₄alkyl, halogen, and —NR^(M)R^(N);    -   R² is —C₁₋₅alkyl, —C₁₋₅alkoxy, —C₇cycloalkyl, C₅₋₇cycloalkyl        substituted with halo or spirocycloalkyl, or aryl;    -   R³ is —R^(A)—R^(B) or halo;        -   wherein R^(A) is ethynyl or is a phenyl or pyridinyl moiety            optionally substituted with one or two Z in which each Z is            independently halogen, —C₁₋₃alkyl, —C₁₋₃haloalkyl,            —C₁₋₃alkoxy, or cyano; and        -   wherein R^(B) is hydrogen, —C₁₋₆alkyl,            —C₀₋₃alkyl-NR^(M)R^(N), —NHC₁₋₃alkyl-R^(Q),            —N(R^(U))C(O)—R^(Q), —C(O)NR^(U)R^(Q), carboxyl,            —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₃alkyl-C₃₋₆cycloalkyl,            -methyl-(C₁₋₄alkoxy)₁₋₂, —C₀₋₃alkyl-NR^(S)R^(T),            —C₃₋₇cycloalkyl-C₀₋₃alkyl-R^(Q), —C₂₋₆alkynylR^(Q), or            —C₂₋₄alkenyl-R^(Q);            -   wherein R^(Q) is a 5- to 9-membered monocyclic or                bicyclic aryl or heteroaryl or a 3- to 7-membered                cycloalkyl or heterocycloalkyl, optionally substituted                with one or two R^(Z), in which each R^(Z) is                independently —C₁₋₃alkyl, —C₁₋₃alkoxy, oxo, or                —NR^(M)R^(N);            -   R^(S) and R^(T) are each independently hydrogen or                —C₁₋₄alkyl, or one of R^(S) and R^(T) is hydrogen and                the other is —C(O)-5- to 9-membered aryl or heteroaryl;                and            -   R^(U) is hydrogen or —C₁₋₄alkyl;    -   provided that, when R^(A) is phenyl, then R^(B) appears at the        para or meta position relative to the thiophene moiety; and    -   R⁴ is hydrogen, —C₁₋₄alkyl, —C₁₋₄alkyl-OC(O)O—C₁₋₄alkyl,        —C₁₋₄alkyl-OC(O)—C₁₋₄alkyl, —C₁₋₄alkyl-OC(O)O—C₃₋₆cycloalkyl,        5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl-, —C₀₋₃alkyl-C₅₋₆aryl, or        —C₁₋₄alkyl-NR^(V)R^(W); and        -   R^(V) and R^(W) are independently hydrogen or —C₁₋₄alkyl.

In some embodiments, the invention provides compounds in which R² is—C₁₋₅alkyl substituted with 1-5 halogens. In some embodiments, R² isphenyl substituted with 1 or 2 halogens or —C₁₋₃alkyl groups optionallysubstituted with 1-3 halogens.

In another aspect, the invention provides compounds according to FormulaI:

and salts and solvates thereof,wherein:

-   -   one of X and Y is —CH₂— and the other is —NR¹—;    -   R¹ is hydrogen, —C₁₋₄alkyl, —C₁₋₆hydroxyalkyl, —C₁₋₄haloalkyl,        —C₁₋₄alkyl-O—C₁₋₄alkyl, —S(O)₂—C₀₋₄alkyl-R^(O),        —C₀₋₄alkyl-S(O)₂—C₁₋₄alkyl, —C₀₋₄alkyl-S(O)₂—NR^(M)R^(N),        —C₂₋₄alkyl-NR^(M)R^(N), —C₀₋₃alkyl-C(O)C₁₋₄alkyl,        —C₀₋₃alkyl-C(O)—C₁₋₄hydroxyalkyl,        —C₀₋₃alkyl-C(O)—C₀₋₄alkyl-R^(O), —C(O)O—C₁₋₄alkyl,        —C₀₋₃alkyl-C(O)O—C₀₋₄alkyl-R^(O), —C₀₋₄alkyl-C(O)OH, or        —C₀₋₃alkyl-C(O)—C₀₋₄alkyl-NR^(M)R^(N);        -   wherein:            -   R^(M) and R^(N) are independently hydrogen, —C₁₋₄alkyl,                or R^(M) and R^(N) together with the atoms to which they                are attached can form a 4- to 6-membered ring; and            -   R^(O) is a 5- to 7-membered cycloalkyl or                heterocycloalkyl group, optionally substituted with a                hydroxyl, —C₁₋₃alkyl, aryl, —O-aryl, or —NR^(M)R^(N)                moiety, or is a 6- to 10-membered aryl or a 5- to                10-membered heteroaryl, in each case monocyclic or                bicyclic, and optionally substituted with (a) one to                three moieties independently selected from —C₁₋₄alkyl,                halogen, —NR^(M)R^(N), —C₁₋₄haloalkyl, —C₁₋₄alkoxy,                —C₁₋₄hydroxyalkyl, cyano, —O-aryl, and aryl, or (b) a                6-membered aryl or 5-6 membered heteroaryl, optionally                substituted with one to three moieties independently                selected from —C₁₋₄alkyl, halogen, and —NR^(M)R^(N);    -   R² is —C₁₋₅alkyl, —C₅₋₇cycloalkyl-C₀₋₃alkyl in which the alkyl        is optionally substituted with 1-3 halogens,        —C₅₋₇cycloalkenyl-C₀₋₃alkyl in which the alkyl moiety is        optionally substituted with 1-3 halogens,        —C₁₋₄alkyl-C₃₋₅cycloalkyl, or phenyl optionally substituted with        1 or 2 halogens or —C₁₋₃alkyl groups optionally substituted with        1-3 halogens;    -   R³ is —R^(A)—R^(B);        -   wherein R^(A) is ethynyl or is a phenyl substituted with            Z_(m) in which m=1 or 2 and each Z is independently halogen,            —C₁₋₃alkyl, —C₁₋₃haloalkyl, —C₁₋₃alkoxy, or cyano, provided,            however, that, if m=1, then Z is not a halogen, and if m=2,            then at least one Z is not a halogen; and        -   wherein R^(B) is hydrogen, —C₁₋₆alkyl,            —C₀₋₃alkyl-NR^(M)R^(N), —NHC₁₋₃alkyl-R^(Q),            —N(R^(U))C(O)—R^(Q), —C(O)NR^(U)R^(Q), carboxyl,            —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₃alkyl-C₃₋₆cycloalkyl,            —C₁₋₄alkoxy, -methyl-(C₁₋₄alkoxy)₁₋₂,            —C₀₋₃alkyl-NR^(S)R^(T), —C₃₋₇cycloalkyl-C₀₋₃alkyl-R^(Q),            —C₀₋₄alkyl-R^(Q), —C₂₋₆alkynylR^(Q), or —C₂₋₄alkenyl-R^(Q);            -   wherein R^(Q) is a 5- to 9-membered monocyclic or                bicyclic aryl or heteroaryl or a 3- to 7-membered                cycloalkyl or heterocycloalkyl, optionally substituted                with one or two R^(Z), in which each R^(Z) is                independently —C₁₋₃alkyl, —C₁₋₃alkoxy, oxo, or                —NR^(M)R^(N);            -   R^(S) and R^(T) are each independently hydrogen or                —C₁₋₄alkyl, or one of R^(S) and R^(T) is hydrogen and                the other is —C(O)-5- to 9-membered aryl or heteroaryl;                and            -   R^(U) is hydrogen or —C₁₋₄alkyl;    -   provided that, when R^(A) is phenyl, then R^(B) appears at the        para or meta position relative to the thiophene moiety;    -   R⁴ is hydrogen, —C₁₋₄alkyl, —C₁₋₄alkyl-OC(O)O—C₁₋₄alkyl,        —C₁₋₄alkyl-OC(O)—C₁₋₄alkyl, —C₁₋₄alkyl-OC(O)O—C₃₋₆cycloalkyl,        5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl-, —C₀₋₃alkyl-C₅₋₆aryl, or        —C₁₋₄alkyl-NR^(V)R^(W); and        -   R^(V) and R^(W) are independently hydrogen or —C₁₋₄alkyl.

In another aspect, the invention provides compounds according to FormulaVI:

and salts and solvates thereof,wherein:

-   -   one of X and Y is —CH₂— and the other is —NR¹—;    -   R¹ is hydrogen, —C₁₋₄alkyl, —C₁₋₆hydroxyalkyl, —C₁₋₄haloalkyl,        —C₁₋₄alkyl-O—C₁₋₄alkyl, —S(O)₂—C₀₋₄alkyl-R^(O),        —C₀₋₄alkyl-S(O)₂—C₁₋₄alkyl, —C₀₋₄alkyl-S(O)₂—NR^(M)R^(N),        —C₂₋₄alkyl-NR^(M)R^(N), —C₀₋₄alkyl-R^(O),        —C₀₋₃alkyl-C(O)C₁₋₄alkyl, —C₀₋₃alkyl-C(O)—C₁₋₄hydroxyalkyl,        —C₀₋₃alkyl-C(O)—C₀₋₄alkyl-R^(O), —C(O)O—C₁₋₄alkyl,        —C₀₋₃alkyl-C(O)O—C₀₋₄alkyl-R^(O), —C₀₋₄alkyl-C(O)OH, or        —C₀₋₃alkyl-C(O)—C₀₋₄alkyl-NR^(M)R^(N);        -   wherein:            -   R^(M) and R^(N) are independently hydrogen, —C₁₋₄alkyl,                or R^(M) and R^(N) together with the atoms to which they                are attached can form a 4- to 6-membered ring; and            -   R^(O) is a 5- to 7-membered cycloalkyl or                heterocycloalkyl group, optionally substituted with a                hydroxyl, —C₁₋₃alkyl, aryl, —O-aryl, or —NR^(M)R^(N)                moiety, or is a 6- to 10-membered aryl or a 5- to                10-membered heteroaryl, in each case monocyclic or                bicyclic, and optionally substituted with (a) one to                three moieties independently selected from —C₁₋₄alkyl,                halogen, —NR^(M)R^(N), —C₁₋₄haloalkyl, —C₁₋₄alkoxy,                —C₁₋₄hydroxyalkyl, cyano, —O-aryl, and aryl, or (b) a                6-membered aryl or 5-6 membered heteroaryl, optionally                substituted with one to three moieties independently                selected from —C₁₋₄alkyl, halogen, and —NR^(M)R^(N);    -   R² is —C₁₋₅alkyl optionally substituted with 1-5 halogens,        —C₁₋₅alkoxy, —C₅₋₇cycloalkyl-C₀₋₃alkyl in which the alkyl is        optionally substituted with 1-3 halogens,        —C₅₋₇cycloalkenyl-C₀₋₃alkyl in which the alkyl moiety is        optionally substituted with 1-3 halogens,        —C₁₋₄alkyl-C₃₋₅cycloalkyl, or phenyl optionally substituted with        1 or 2 halogens or —C₁₋₃alkyl groups optionally substituted with        1-3 halogens;    -   R³ is -A-R^(B);        -   wherein the A ring is 2-, 3-, or 4-pyridinyl, in which each            Z is independently halogen, —C₁₋₃alkyl, —C₁₋₃haloalkyl,            —C₁₋₃alkoxy, or cyano; and        -   wherein R^(B) is hydrogen, —C₁₋₆alkyl,            —C₀₋₃alkyl-NR^(M)R^(N), —NHC₁₋₃alkyl-R^(Q),            —N(R^(U))C(O)—R^(Q), —C(O)NR^(U)R^(Q), carboxyl,            —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₃alkyl-C₃₋₆cycloalkyl,            —C₁₋₄alkoxy, -methyl-(C₁₋₄alkoxy)₁₋₂,            —C₀₋₃alkyl-NR^(S)R^(T), —C₃₋₇cycloalkyl-C₀₋₃alkyl-R^(Q),            —C₀₋₄alkyl-R^(Q), —C₂₋₆alkynylR^(Q), or —C₂₋₄alkenyl-R^(Q);            -   wherein R^(Q) is a 5- to 9-membered monocyclic or                bicyclic aryl or heteroaryl or a 3- to 7-membered                cycloalkyl or heterocycloalkyl, optionally substituted                with one or two R^(Z), in which each R^(Z) is                independently —C₁₋₃alkyl, —C₁₋₃alkoxy, oxo, or                —NR^(M)R^(N); and            -   R^(S) and R^(T) are each independently hydrogen or                —C₁₋₄alkyl, or one of R^(S) and R^(T) is hydrogen and                the other is —C(O)-5- to 9-membered aryl or heteroaryl;    -   R⁴ is hydrogen, —C₁₋₄alkyl, —C₁₋₄alkyl-OC(O)O—C₁₋₄alkyl,        —C₁₋₄alkyl-OC(O)—C₁₋₄alkyl, —C₁₋₄alkyl-OC(O)O—C₃₋₆cycloalkyl,        5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl-, —C₀₋₃alkyl-C₅₋₆aryl, or        —C₁₋₄alkyl-NR^(V)R^(W); and        -   R^(V) and R^(W) are independently hydrogen or —C₁₋₄alkyl.

The general Formula VI includes, for example, compounds of generalFormulas VIa-VIf:

and salts (e.g., pharmaceutically acceptable salts) and solvatesthereof, in which m=0, 1, or 2, and any of the attached functionalgroups may be as otherwise set forth herein for compounds of Formula I.In some embodiments, these compounds have general Formula VIa. In someembodiments, these compounds have general Formula VIb. In someembodiments, Z occurs once, and is a halogen. In some embodiments Zoccurs once and is —C₁₋₃alkyl, —C₁₋₃haloalkyl, —C₁₋₃alkoxy, or cyano. Insome embodiments, Z occurs twice, in which each Z is independentlyhalogen, —C₁₋₃alkyl, —C₁₋₃haloalkyl, —C₁₋₃alkoxy, or cyano.

In another aspect, the invention provides compounds according to FormulaI:

and salts and solvates thereof,wherein:

-   -   one of X and Y is —CH₂— and the other is —NR¹—;    -   R¹ is hydrogen, —C₁₋₄alkyl, —C₁₋₆hydroxyalkyl, —C₁₋₄haloalkyl,        —C₁₋₄alkyl-O—C₁₋₄alkyl, —S(O)₂—C₀₋₄alkyl-R^(O),        —C₀₋₄alkyl-S(O)₂—C₁₋₄alkyl, —C₀₋₄alkyl-S(O)₂—NR^(M)R^(N),        —C₂₋₄alkyl-NR^(M)R^(N), —C₀₋₄alkyl-R^(O),        —C₀₋₃alkyl-C(O)C₁₋₄alkyl, —C₀₋₃alkyl-C(O)—C₁₋₄hydroxyalkyl,        —C₀₋₃alkyl-C(O)—C₀₋₄alkyl-R^(O), —C(O)O—C₁₋₄alkyl,        —C₀₋₃alkyl-C(O)O—C₀₋₄alkyl-R^(O), —C₀₋₄alkyl-C(O)OH, or        —C₀₋₃alkyl-C(O)—C₀₋₄alkyl-NR^(M)R^(N);        -   wherein:            -   R^(M) and R^(N) are independently hydrogen, —C₁₋₄alkyl,                or R^(M) and R^(N) together with the atoms to which they                are attached can form a 4- to 6-membered ring; and            -   R^(O) is a 5- to 7-membered cycloalkyl or                heterocycloalkyl group, optionally substituted with a                hydroxyl, —C₁₋₃alkyl, aryl, —O-aryl, or —NR^(M)R^(N)                moiety, or is a 6- to 10-membered aryl or a 5- to                10-membered heteroaryl, in each case monocyclic or                bicyclic, and optionally substituted with (a) one to                three moieties independently selected from —C₁₋₄alkyl,                halogen, —NR^(M)R^(N), —C₁₋₄haloalkyl, —C₁₋₄alkoxy,                —C₁₋₄hydroxyalkyl, cyano, aryl, —O-aryl, and aryl,                or (b) a 6-membered aryl or 5-6 membered heteroaryl,                optionally substituted with one to three moieties                independently selected from —C₁₋₄alkyl, halogen, and                —NR^(M)R^(N);    -   R² is —C₁₋₅alkyl optionally substituted with 1-5 halogens,        —C₁₋₅alkoxy, —C₅₋₇cycloalkyl-C₀₋₃alkyl in which the alkyl is        optionally substituted with 1-3 halogens,        —C₅₋₇cycloalkenyl-C₀₋₃alkyl in which the alkyl moiety is        optionally substituted with 1-3 halogens,        —C₁₋₄alkyl-C₃₋₅cycloalkyl, or phenyl optionally substituted with        1 or 2 halogens or —C₁₋₃alkyl groups optionally substituted with        1-3 halogens;    -   R³ is —R^(A)—R^(B) or halo;        -   wherein R^(A) is ethynyl or is a phenyl or pyridinyl moiety            optionally substituted with one or two Z in which each Z is            independently halogen, —C₁₋₃alkyl, —C₁₋₃haloalkyl,            —C₁₋₃alkoxy, or cyano; and        -   wherein R^(B) is hydrogen, —C₁₋₆alkyl,            —C₀₋₃alkyl-NR^(M)R^(N), —NHC₁₋₃alkyl-R^(Q),            —N(R^(U))C(O)—R^(Q), —C(O)NR^(U)R^(Q), carboxyl,            —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₃alkyl-C₃₋₆cycloalkyl,            —C₁₋₄alkoxy, -methyl-(C₁₋₄alkoxy)₁₋₂,            —C₀₋₃alkyl-NR^(S)R^(T), —C₃₋₇cycloalkyl-C₀₋₃alkyl-R^(Q),            —C₀₋₄alkyl-R^(Q), —C₂₋₆alkynylR^(Q), or —C₂₋₄alkenyl-R^(Q);            -   wherein R^(Q) is a 5- to 9-membered monocyclic or                bicyclic aryl or heteroaryl or a 3- to 7-membered                cycloalkyl or heterocycloalkyl, optionally substituted                with R^(Z) _(n) in which n=1 or 2, and each R^(Z) is                independently —C₁₋₃alkyl, —C₁₋₃alkoxy, oxo, or                —NR^(M)R^(N), provided, however, that, if n=1, then the                R^(Z) is not —C₁₋₃alkyl or —NR^(M)R^(N), and if n=2,                then at least one R^(Z) is not —C₁₋₃alkyl or                —NR^(M)R^(N); and            -   R^(S) and R^(T) are each independently hydrogen or                —C₁₋₄alkyl, or one of R^(S) and R^(T) is hydrogen and                the other is —C(O)-5- to 9-membered aryl or heteroaryl;                and            -   R^(U) is hydrogen or —C₁₋₄alkyl;    -   provided that, when R^(A) is phenyl, then R^(B) appears at the        para or meta position relative to the thiophene moiety; and    -   R⁴ is hydrogen, —C₁₋₄alkyl, —C₁₋₄alkyl-OC(O)O—C₁₋₄alkyl,        —C₁₋₄alkyl-OC(O)—C₁₋₄alkyl, —C₁₋₄alkyl-OC(O)O—C₃₋₆cycloalkyl,        5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl-, —C₀₋₃alkyl-C₅₋₆aryl, or        —C₁₋₄alkyl-NR^(V)R^(W); and        -   R^(V) and R^(W) are independently hydrogen or —C₁₋₄alkyl.

In one aspect, representative compounds of general Formula I, andparticularly general Formula Ia, include, for example:

-   5-(3-methyl-4-(thiazole-4-carboxamido)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylic    acid;-   5-(3-methoxy-4-(thiazole-4-carboxamido)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylic    acid;-   5-(3-cyano-4-(thiazole-4-carboxamido)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylic    acid;-   5-(3-ethyl-4-(thiazole-4-carboxamido)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylic    acid;-   3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-(4-(thiazole-4-carboxamido)-3-(trifluoromethyl)phenyl)thiophene-2-carboxylic    acid;-   5-(4-(5-methoxypyrazolo[1,5-a]pyrimidin-2-yl)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylic    acid;-   3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-(4-(4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)phenyl)thiophene-2-carboxylic    acid;-   5-(3-methyl-4-(pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylic    acid;-   3-(1-methyl-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(3-methyl-4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylic    acid;-   3-(1-(2-hydroxyethyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(3-methyl-4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylic    acid;-   3-(1-((l-methyl-1H-pyrazol-4-yl)methyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(3-methyl-4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylic    acid;-   3-(4-(4,4-difluorocyclohexyl)-1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylic    acid;-   3-(5-(2,4-dichlorophenyl)-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylic    acid;-   3-(1-methyl-5-(p-tolyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylic    acid;-   5-(6-aminopyridin-3-yl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylic    acid;-   3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-(6-(thiazole-4-carboxamido)pyridin-3-yl)thiophene-2-carboxylic    acid;-   3-(5-cycloheptyl-1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-phenyl-thiophene-2-carboxylic    acid;-   3-[5-(4-chloro-phenyl)-1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylic    acid;-   3-(1-methyl-5-pentyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-phenyl-thiophene-2-carboxylic    acid;    and salts (e.g., pharmaceutically acceptable salts) and solvates    thereof.

In another aspect, the invention provides compounds represented by thegeneral Formula I:

and salts and solvates thereof, wherein:

-   -   one of X and Y is —CH₂— and the other is —NR¹—;    -   R¹ is hydrogen, —C₁₋₄alkyl, —C₁₋₆hydroxyalkyl, —C₁₋₄haloalkyl,        —C₁₋₄alkyl-O—C₁₋₄alkyl, —S(O)₂—C₀₋₄alkyl-R^(O),        —C₀₋₄alkyl-S(O)₂—C₁₋₄alkyl, —C₀₋₄alkyl-S(O)₂—NR^(M)R^(N),        —C₂₋₄alkyl-NR^(M)R^(N), —C₀₋₄alkyl-R^(O),        —C₀₋₃alkyl-C(O)C₁₋₄alkyl, —C₀₋₃alkyl-C(O)—C₁₋₄hydroxyalkyl,        —C₀₋₃alkyl-C(O)—C₀₋₄alkyl-R^(O), —C(O)O—C₁₋₄alkyl,        —C₀₋₃alkyl-C(O)O—C₀₋₄alkyl-R^(O), —C₀₋₄alkyl-C(O)OH, or        —C₀₋₃alkyl-C(O)—C₀₋₄alkyl-NR^(M)R^(N);        -   wherein:            -   R^(M) and R^(N) are independently hydrogen, —C₁₋₄alkyl,                or R^(M) and R^(N) together with the atoms to which they                are attached can form a 4- to 6-membered ring; and            -   R^(O) is a 3- to 7-membered cycloalkyl or 5- to                7-membered heterocycloalkyl, or is a 6- to 10-membered                aryl or a 5- to 10-membered heteroaryl, in each case                monocyclic or bicyclic;    -   R² is —C₁₋₅alkyl, —C₁₋₅alkoxy, —C₅₋₇cycloalkyl-C₀₋₃alkyl,        —C₅₋₇cycloalkenyl-C₀₋₃alkyl, —C₁₋₄alkyl-C₃₋₅cycloalkyl, or        phenyl;    -   R³ is —R^(A)—R^(B) or halo;        -   wherein R^(A) is an ethynyl, or is a phenyl or pyridinyl            moiety; and        -   wherein R^(B) is hydrogen, —C₁₋₆alkyl,            —C₀₋₃alkyl-NR^(M)R^(N), —NHC₁₋₃alkyl-R^(Q),            —N(R^(U))C(O)—R^(Q), —C(O)NR^(U)R^(Q), carboxyl,            —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₃alkyl-C₃₋₆cycloalkyl,            —C₁₋₄alkoxy, -methyl-(C₁₋₄alkoxy)₁₋₂,            —C₀₋₃alkyl-NR^(S)R^(T), —C₃₋₇cycloalkyl-C₀₋₃alkyl-R^(Q),            —C₀₋₄alkyl-R^(Q), —C₂₋₆alkynylR^(Q), or —C₂₋₄alkenyl-R^(Q);            -   wherein R^(Q) is a 5- to 9-membered monocyclic or                bicyclic aryl or heteroaryl or a 3- to 7-membered                cycloalkyl or heterocycloalkyl;            -   R^(S) and R^(T) are each independently hydrogen or                —C₁₋₄alkyl, or one of R^(S) and R^(T) is hydrogen and                the other is —C(O)-5- to 9-membered aryl or heteroaryl;                and            -   R^(U) is hydrogen or —C₁₋₄alkyl;    -   provided that, when R^(A) is phenyl, then R^(B) appears at the        para or meta position relative to the thiophene moiety; and    -   R⁴ is hydrogen, —C₁₋₄alkyl, —C₁₋₄alkyl-OC(O)O—C₁₋₄alkyl,        —C₁₋₄alkyl-OC(O)—C₁₋₄alkyl, —C₁₋₄alkyl-OC(O)O—C₃₋₆cycloalkyl,        5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl-, —C₀₋₃alkyl-C₅₋₆aryl, or        —C₁₋₄alkyl-NR^(U)R^(V); and        -   R^(V) and R^(W) are independently hydrogen or —C₁₋₄alkyl.

In some embodiments, the invention provides compounds of Formula I, inwhich X is —NR¹— and Y is —CH₂—. Thus, the invention provides compoundsrepresented by the general Formula II:

and salts (e.g., pharmaceutically acceptable salts) and solvatesthereof, in which any of the attached functional groups may be asotherwise set forth herein for compounds of Formula I.

In some embodiments, the invention provides compounds of Formula I inwhich X is —CH₂— and Y is —NR¹—. Thus, the invention provides compoundsrepresented by the general Formula III:

and salts (e.g., pharmaceutically acceptable salts) and solvatesthereof, in which any of the attached functional groups may be asotherwise set forth herein for compounds of Formula I.

In some embodiments, the invention provides compounds of Formula I, inwhich R^(O) is a 3- to 7-membered cycloalkyl or 5- to 7-memberedheterocycloalkyl, optionally substituted with a hydroxyl, —C₁₋₃alkyl,aryl, —O-aryl, or —NR^(M)R^(N).

In some embodiments, the invention provides compounds of Formula I, inwhich R^(O) is a 6- to 10-membered aryl or a 5- to 10-memberedheteroaryl, in each case monocyclic or bicyclic, substituted with one tothree moieties independently selected from —C₁₋₄alkyl, halogen,—NR^(M)R^(N), —C₁₋₄haloalkyl, —C₁₋₄alkoxy, —C₁₋₄hydroxyalkyl, cyano,—O-aryl, and aryl.

In some embodiments, the invention provides compounds of Formula I, inwhich R^(O) is a 6-membered aryl or 5-6 membered heteroaryl, substitutedwith one to three moieties independently selected from —C₁₋₄alkyl,halogen, and —NR^(M)R^(N).

In some embodiments, the invention provides compounds of Formula I inwhich R^(A) is ethynyl.

In some embodiments, the invention provides compounds of Formula I inwhich R^(A) is ethynyl, and R^(B) is selected from —C₁₋₆alkyl, and—C₀₋₃alkyl-C₃₋₆cycloalkyl.

In some embodiments, the invention provides compounds of Formula I inwhich R^(A) is phenyl. In some embodiments, the invention providescompounds of Formula I in which R^(A) is phenyl and R^(B) appears at thepara position relative to the thiophene moiety. In some embodiments, theinvention provides compounds of Formula I, in which R^(A) is phenyl andR^(B) is —C₂₋₆alkynyl-R^(Q), or —C₂₋₄alkenyl-R^(Q).

In some embodiments, the invention provides compounds of Formula I, inwhich R^(A) is ethynyl and R^(B) is hydrogen, —C₁₋₆alkyl,—C₃₋₇cycloalkyl-C₀₋₃alkyl-R^(Q).

In some embodiments, the invention provides compounds of Formula I inwhich R^(A) is phenyl and R^(B) is selected from —NHC₁₋₃alkyl-R^(Q),—NHC(O)—R^(Q), —C(O)NH—R^(Q), —C₀₋₄alkyl-R^(Q), or —C₂₋₄alkenyl-R^(Q).

In some embodiments, the invention provides compounds of Formula I inwhich R^(A) is a phenyl or pyridinyl, substituted with one or two Z inwhich each Z is independently halogen, —C₁₋₃alkyl, —C₁₋₃haloalkyl,—C₁₋₃alkoxy, or cyano.

In some embodiments, the invention provides compounds of Formula I, inwhich R^(Q) is a 5- to 9-membered monocyclic or bicyclic aryl orheteroaryl or a 3- to 7-membered cycloalkyl or heterocycloalkyl,substituted with one or two —C₁₋₃alkyl, —C₁₋₃alkoxy, oxo, or—NR^(M)R^(N).

In some embodiments, the invention provides compounds of Formula I, inwhich R² is —C₁₋₅alkyl, substituted with 1-5 halogens. In someembodiments, the invention provides compounds of Formula I, in which R²is —C₅₋₇cycloalkyl-C₀₋₃alkyl, in which the alkyl is substituted with 1-3halogens. In some embodiments, the invention provides compounds ofFormula I, in which R² is —C₅₋₇cycloalkenyl-C₀₋₃alkyl, in which thealkyl moiety is substituted with 1-3 halogens. In some embodiments, theinvention provides compounds of Formula I, in which R² is phenyl,substituted with 1 or 2 halogens or —C₁₋₃alkyl groups optionallysubstituted with 1-3 halogens.

In some embodiments, the invention provides compounds of Formula I inwhich R² is —C₅₋₇cycloalkyl-C₀₋₃alkyl in which the alkyl is optionallysubstituted with 1-3 halogens. In some embodiments, the inventionprovides compounds of Formula I in which R² is -cyclohexylmethyl.Accordingly, the general Formula I encompasses compounds of generalFormula IV:

and salts (e.g., pharmaceutically acceptable salts) and solvatesthereof, in which any of the attached functional groups may be asotherwise set forth herein for compounds of Formula I. In someembodiments, the invention provides compounds of Formula I in which R²is —C₁₋₅alkyl, or R² is —C₅₋₆cycloalkyl-C₀₋₃alkyl in which the alkyl isoptionally substituted with 2-3 halogens, or R² is—C₇cycloalkyl-C₀₋₃alkyl in which the alkyl is optionally substitutedwith 1-3 halogens, or R² is —C₅₋₆cycloalkenyl-C₀₋₃alkyl in which thealkyl is optionally substituted with 2-3 halogens, or R² is—C₇cycloalkenyl-C₀₋₃alkyl in which the alkyl is optionally substitutedwith 1-3 halogens. In some embodiments, the invention provides compoundsof Formula I in which R² is phenyl optionally substituted with 1 or 2moieities independently selected from halogens and —C₁₋₃alkyl groupsoptionally substituted with 1-3 halogens.

In some embodiments, the invention provides compounds of Formula I inwhich R^(A) is phenyl, optionally substituted with 1 or 2 Z moieties, inwhich each Z is independently halogen, —C₁₋₃alkyl, —C₁₋₃haloalkyl,—C₁₋₃alkoxy, or cyano. Accordingly, the general Formula I encompassescompounds of general Formula V:

and salts (e.g., pharmaceutically acceptable salts) and solvatesthereof, in which any of the attached functional groups may be asotherwise set forth herein for compounds of Formula I.

The general Formula V includes, for example, compounds of generalFormulas Va and Vb:

and salts (e.g., pharmaceutically acceptable salts) and solvatesthereof, in which any of the attached functional groups may be asotherwise set forth herein for compounds of Formula I. In someembodiments, these compounds have general Formula Va. In someembodiments, these compounds have general Formula Vb. In someembodiments, Z occurs once, and is a halogen. In some embodiments Zoccurs once and is —C₁₋₃alkyl, —C₁₋₃haloalkyl, —C₁₋₃alkoxy, or cyano. Insome embodiments, Z occurs twice, in which each Z is independentlyhalogen, —C₁₋₃alkyl, —C₁₋₃haloalkyl, —C₁₋₃alkoxy, or cyano.

In some embodiments, the invention provides compounds of Formula I inwhich:

-   -   R¹ is hydrogen, —C₁₋₄alkyl, —C₁₋₃alkyl-C₃₋₆cycloalkyl,        —C₁₋₄hydroxyalkyl, —C₂₋₄alkyl-NR^(M)R^(N), —C₁₋₄alkyl ester, or        —C₁₋₃alkyl-C₆₋₁₀aryl; and        -   R^(M) and R^(N) are independently hydrogen, —C₁₋₄alkyl, or            R^(M) and R^(N) together with the atoms to which they are            attached can form a 4- to 6-membered ring.

In some embodiments, the invention provides compounds of Formula I inwhich R¹ is —C₁₋₄alkyl, —C₁₋₃alkyl-C₃₋₆cycloalkyl, —C₁₋₄hydroxyalkyl, or—C₂₋₄alkyl-NR^(M)R^(N).

In some embodiments, the invention provides compounds of Formula I inwhich R^(B) is —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —C₁₋₄alkoxy, or-methyl-(C₁₋₄alkoxy)₁₋₂.

In some embodiments, the invention provides compounds of Formula I inwhich R¹ is —C₁₋₄ alkyl.

In some embodiments, the invention provides compounds of Formula I inwhich R¹—C₁₋₄alkyl-R^(O), in which R^(O) is (optionally substituted)pyridine, pyrazole, or dioxolane.

In some embodiments, the invention provides compounds of Formula I inwhich R^(A) is phenyl and in which R^(B) is —NH—R^(Q) or —NHC(O)—R^(Q)and appears at the para position relative to the thiophene moiety. Insome specific embodiments, R^(A) is phenyl and R^(B) is —NHC(O)—R^(Q)and appears at the para position relative to the thiophene moiety, andR^(Q) is a 5-9 membered heteroaryl, optionally substituted withC₁₋₄alkyl, and R^(A) is optionally substituted with one or more ofC₁₋₄alkyl, C₁₋₄alkoxy, cyano, halogen, and C₁₋₄haloalkyl (e.g.,trifluromethyl).

In some embodiments, the invention provides compounds of Formula I, inwhich R^(Q) contains a 5- to 9-membered aryl or heteroaryl moietyselected from among furyl, isoxazolyl, oxazolyl, phenyl, pyrazolyl,pyridinyl, thiazolyl, thiophenyl, or tetrahydrofuranyl in each caseoptionally substituted with —C₁₋₄alkyl. In some embodiments, R^(Q) is—C₁₋₃alkoxy.

In some embodiments, the invention provides compounds of Formula I inwhich R^(A) is ethynyl and wherein R^(B) is —C₁₋₆alkyl, —C₃₋₆cycloalkyl,—C₁₋₄alkoxy, or -methyl-(C₁₋₄alkoxy)₁₋₂.

In some embodiments, the invention provides compounds of Formula I inwhich R^(B) is not hydrogen, but may be any of the other groupsdescribed herein for that moiety. For example, the invention providescompounds of Formula V, such as compounds of Formula Va or Formula Vb inwhich R^(B) is not hydrogen, but may be any of the other groupsdescribed herein for that moiety. Thus, in some embodiments, forexample, in compounds of Formula V, R^(B) is —C₁₋₆alkyl,—C₀₋₃alkyl-NR^(M)R^(N), —NHC₁₋₃alkyl-R^(Q), —N(R^(U))C(O)—R^(Q),—C(O)NR^(U)R^(Q), carboxyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₂₋₆alkynylR^(Q), —C₀₋₃alkyl-C₃₋₆cycloalkyl, —C₁₋₄alkoxy,-methyl-(C₁₋₄alkoxy)₁₋₂, —C₀₋₃alkyl-NR^(S)R^(T),—C₃₋₇cycloalkyl-C₀₋₃alkyl-R^(Q), —C₀₋₄alkyl-R^(Q), or—C₂₋₄alkenyl-R^(Q); wherein:

-   -   R^(Q) is a 5- to 9-membered monocyclic or bicyclic aryl or        heteroaryl or a 3- to 7-membered cycloalkyl or heterocycloalkyl,        optionally substituted with one or two —C₁₋₃alkyl or        —NR^(M)R^(N);    -   R^(S) and R^(T) are each independently hydrogen or —C₁₋₄alkyl,        or one of R^(S) and R^(T) is hydrogen and the other is —C(O)-5-        to 9-membered aryl or heteroaryl; and    -   R^(U) is hydrogen or —C₁₋₄alkyl

In some embodiments, for example, in compounds of Formula V, when R^(B)is hydrogen, then R¹ is —C₁₋₄alkyl, —C₁₋₄alkyl-C₃₋₇cycloalkyl,—C₀₋₃alkyl-C₅₋₇heterocycloalkyl, —C₁₋₄hydroxyalkyl, —C₁₋₄haloalkyl,—C₁₋₄alkyl-O—C₁₋₄alkyl, —S(O)₂C₁₋₄alkyl, —S(O)₂—R^(P),—S(O)₂C₅₋₇aryl-C₀₋₃alkyl, —C₁₋₄alkyl-S(O)₂R^(L), —C₂₋₄alkyl-NR^(M)R^(N),—C₀₋₃alkyl-C(O)—C₀₋₄alkyl-R^(P), —C(O)O—C₁₋₄alkyl; wherein

-   -   R^(L) is —C₁₋₄alkyl, —C₃₋₅cycloalkyl, —NR^(M)R^(N);    -   R^(M) and R^(N) are independently hydrogen, —C₁₋₄alkyl, or R^(M)        and R^(N) together with the atoms to which they are attached can        form a 4- to 6-membered ring; and    -   R^(O) is a 5- to 6-membered cycloalkyl or heterocycloalkyl, 5-        to 7-membered aryl, or 5- to 10-membered heteroaryl group,        optionally substituted with a hydroxyl, —C₁₋₃alkyl, aryl,        O-aryl, or —NR^(M)R^(N).

In some embodiments, for example, in compounds of Formula V, when R^(B)is hydrogen, then R¹ is hydrogen, —C₁₋₄alkyl, —C₁₋₃alkyl-C₃₋₆cycloalkyl,—C₁₋₄hydroxyalkyl, —C₂₋₄alkyl-NR^(M)R^(N), —S(O)₂C₁₋₄alkyl,—S(O)₂C₄₋₇aryl, —S(O)₂C₆₋₁₀aryl-C₁₋₃alkyl, —C₁₋₄alkyl ester,—C₁₋₄alkyl-S(O)₂R^(L), or —C₁₋₃alkyl-C₆₋₁₀aryl; wherein

-   -   R^(L) is —C₁₋₄alkyl, —C₃₋₅cycloalkyl, or —NR^(M)R^(N); and    -   R^(M) and R^(N) are independently hydrogen, —C₁₋₄alkyl, or R^(M)        and R^(N) together with the atoms to which they are attached can        form a 4- to 6-membered ring.

In some specific sets of embodiments, the compounds of general Formula Vinclude compounds wherein R³ is unsubstituted phenyl, R⁴ is hydrogen or—C₁₋₄alkyl, X is —NR¹—, and Y is —CH₂—. In such cases, R² is other than—C₅₋₆cycloalkyl-C₁₋₃alkyl, or in some cases is other thanC₆cycloalkyl-C₁alkyl. In some embodiments, provided herein are methodsof inhibiting hepatitis C virus polymerase using a compound of Formula Vwherein R³ is unsubstituted phenyl R⁴ is hydrogen or —C₁₋₄alkyl, —NR¹—,and Y is —CH₂ ⁻, -and R² is —C₅₋₆cycloalkyl-C₁₋₃alkyl, or in some casesis C₆cycloalkyl-C₁alkyl.

In some embodiments, the compounds of general Formula V specificallyexclude compounds having a structure:

In some embodiments, provided herein are methods of inhibiting hepatitisC virus polymerase using the specific compounds of Formula V noteddirectly above in this same paragraph, while in other embodiments,provided are methods of inhibiting hepatitis C virus polymerase using acompound of Formula V that is not one of the specific compounds noteddirectly above in this same paragraph.

In one aspect, the invention provides compounds of Formula I in which R⁴is hydrogen. Thus, general Formula I encompasses compounds of generalFormula Ia:

including salts (e.g., pharmaceutically acceptable salts) and solvatesthereof,wherein:

-   -   one of X and Y is —CH₂— and the other is —NR¹—;    -   R¹ is hydrogen, —C₁₋₄alkyl, —C₁₋₆hydroxyalkyl, —C₁₋₄haloalkyl,        —C₁₋₄alkyl-O—C₁₋₄alkyl, —S(O)₂—C₀₋₄alkyl-R^(O),        —C₀₋₄alkyl-S(O)₂—C₁₋₄alkyl, —C₀₋₄alkyl-S(O)₂—NR^(M)R^(N),        —C₂alkyl-NR^(M)R^(N), —C₀₋₄alkyl-R^(O),        —C₀₋₃alkyl-C(O)C₁₋₄alkyl, —C₀₋₃alkyl-C(O)—C₁₋₄hydroxyalkyl,        —C₀₋₃alkyl-C(O)—C₀₋₄alkyl-R^(O), —C(O)O—C₁₋₄alkyl,        —C₀₋₃alkyl-C(O)O—C₀₋₄alkyl-R^(O), —C₀₋₄alkyl-C(O)OH, or        —C₀₋₃alkyl-C(O)—C₀₋₄alkyl-NR^(M)R^(N);        -   wherein:            -   R^(M) and R^(N) are independently hydrogen, —C₁₋₄alkyl,                or R^(M) and R^(N) together with the atoms to which they                are attached can form a 4- to 6-membered ring; and            -   R^(O) is a 3- to 7-membered cycloalkyl or 5- to                7-membered heterocycloalkyl group, optionally                substituted with a hydroxyl, —C₁₋₃alkyl, aryl, —O— aryl,                or —NR^(M)R^(N) moiety, or is a 6- to 10-membered aryl                or a 5- to 10-membered heteroaryl, in each case                monocyclic or bicyclic, and optionally substituted                with (a) one to three moieties independently selected                from —C₁₋₄alkyl, halogen, —NR^(M)R^(N), —C₁₋₄haloalkyl,                —C₁₋₄alkoxy, —C₁₋₄hydroxyalkyl, cyano, aryl, —O-aryl,                and aryl, or (b) a 6-membered aryl or 5-6 membered                heteroaryl, optionally substituted with one to three                moieties independently selected from —C₁₋₄alkyl,                halogen, and —NR^(M)R^(N);    -   R² is —C₁₋₅alkyl optionally substituted with 1-5 halogens,        —C₁₋₅alkoxy, —C₅₋₇cycloalkyl-C₀₋₃alkyl in which the alkyl is        optionally substituted with 1-3 halogens,        —C₅₋₇cycloalkenyl-C₀₋₃alkyl in which the alkyl moiety is        optionally substituted with 1-3 halogens,        —C₁₋₄alkyl-C₃₋₅cycloalkyl, or phenyl optionally substituted with        1 or 2 halogens or —C₁₋₃alkyl groups optionally substituted with        1-3 halogens;    -   R³ is —R^(A)—R^(B) or halo;        -   wherein R^(A) is an ethynyl, a phenyl or pyridinyl moiety            optionally substituted with one or two Z in which each Z is            independently halogen, —C₁₋₃alkyl, —C₁₋₃haloalkyl,            —C₁₋₃alkoxy, or cyano; and        -   wherein R^(B) is hydrogen, —C₁₋₆alkyl,            —C₀₋₃alkyl-NR^(M)R^(N), —NHC₁₋₃alkyl-R^(Q),            —N(R^(U))C(O)—R^(Q), —C(O)NR^(U)R^(Q), carboxyl,            —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₃alkyl-C₃₋₆cycloalkyl,            —C₁₋₄alkoxy, -methyl-(C₁₋₄alkoxy)₁₋₂,            —C₀₋₃alkyl-NR^(S)R^(T), —C₃₋₇cycloalkyl-C₀₋₃alkyl-R^(Q),            —C₀₋₄alkyl-R^(Q), —C₂₋₆alkynylR^(Q), or —C₂₋₄alkenyl-R^(Q);            -   wherein R^(Q) is a 5- to 9-membered monocyclic or                bicyclic aryl or heteroaryl or a 3- to 7-membered                cycloalkyl or heterocycloalkyl, optionally substituted                with one or two —C₁₋₃alkyl, —C₁₋₃alkoxy, oxo, or                —NR^(M)R^(N);            -   R^(S) and R^(T) are each independently hydrogen or                —C₁₋₄alkyl, or one of R^(S) and R^(T) is hydrogen and                the other is —C(O)-5- to 9-membered aryl or heteroaryl;                and            -   R^(U) is hydrogen or —C₁₋₄alkyl;    -   provided that, when R^(A) is phenyl, then R^(B) appears at the        para or meta position relative to the thiophene moiety.

In some embodiments, disclosed herein are compounds of general Formula Iwherein R^(A) is phenyl, R^(B) is —C₀₋₄alkyl-R^(Q) or —N(H)C(O)—R^(Q),and R^(Q) is a 5-membered monocyclic heteroaryl or 9-membered bicyclicheteroaryl. Further provided are methods of inhibiting hepatitis C viruspolymerase using one or more of these specific compounds of Formula I.

In another aspect, the invention provides compounds of general FormulaIa:

including salts (e.g., pharmaceutically acceptable salts) and solvatesthereof,wherein:

-   -   one of X and Y is —CH₂— and the other is —NR¹—;    -   R¹ is hydrogen, —C₁₋₄alkyl, —C₁₋₃alkyl-C₃₋₆cycloalkyl,        —C₁₋₄hydroxyalkyl, —C₂₋₄alkyl-NR^(M)R^(N), —S(O)₂C₁₋₄alkyl,        —S(O)₂C₄₋₇aryl, —S(O)₂C₆₋₁₀aryl-C₁₋₃alkyl, —C₁₋₄alkyl ester,        —C₀₋₄alkyl-S(O)₂—C₁₋₄alkyl, —C₀₋₄alkyl-S(O)₂—NR^(M)R^(N), or        —C₁₋₃alkyl-C₆₋₁₀aryl; wherein R^(M) and R^(N) are independently        hydrogen, —C₁₋₄alkyl, or R^(M) and R^(N) together with the atoms        to which they are attached can form a 4- to 6-membered ring;    -   R₂ is —C₅₋₆cycloalkyl, —C₅₋₆cycloalkyl-C₁₋₃alkyl,        —C₅₋₆cycloalkenyl, or —C₅₋₆cycloalkenyl-C₁₋₃ alkyl; and    -   R³ is —R^(A)R^(E) or halo;        -   wherein R^(A) is phenyl or ethynyl, and        -   wherein R^(B) is hydrogen, —C₁₋₆alkyl, —NHR^(Q), carboxyl,            —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₂₋₆alkynylR^(Q),            —C₄₋₆cycloalkyl, —C₁₋₄alkoxy, -methyl-(C₁₋₄alkoxy)₁₋₂,            —C₁₋₃alkyl-NR^(S)R^(T), —C₆₋₁₀aryl, or —C₅₋₁₀heteroaryl;            -   wherein R^(Q) is hydrogen, —C(O)-5- to 9-membered                heteroaryl, or —C(O)C₁₋₃alkyl; and            -   R^(S) and R^(T) are each independently hydrogen, or C₁₋₃                alkyl, one of R^(S) and R^(T) is hydrogen and the other                is —C(O)-5- to 9-membered aryl or heteroaryl;                provided that if R^(A) is phenyl, then R^(B) appears at                the para or meta position relative to the thiophene                moiety.

In another aspect, representative compounds of general Formula I, andparticularly general Formula Ia, include, for example:

-   5-(3-chloro-4-(thiazole-4-carboxamido)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylic    acid;-   3-(1-((l-methyl-1H-pyrazol-4-yl)methyl)-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylic    acid;-   3-(1-(2-hydroxyethyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylic    acid;-   3-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylic    acid;-   3-(1-(2,3-dihydroxypropyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylic    acid;-   3-(1-(2-hydroxyethyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)thiophene-2-carboxylic    acid;-   3-(1-(2,3-dihydroxypropyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)thiophene-2-carboxylic    acid;-   3-(1-((l-methyl-1H-pyrazol-4-yl)methyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylic    acid;-   3-(1-((l-methyl-1H-pyrazol-4-yl)methyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)thiophene-2-carboxylic    acid;-   3-(1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylic    acid;-   5-(3-fluoro-4-(thiazole-4-carboxamido)phenyl)-3-(1-methyl-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)thiophene-2-carboxylic    acid;-   3-(5-cyclohexyl-1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylic    acid;-   3-(5-cyclopentyl-1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-phenyl-thiophene-2-carboxylic    acid;-   3-(4-cyclohexyl-1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylic    acid;-   3-(5-cyclohexyl-1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid;    and salts (e.g., pharmaceutically acceptable salts) and solvates    thereof.

The invention further provides compounds that can be useful as prodrugs.For example, the carboxyl group on the central thiophene moiety of thecompounds of Formula Ia may be modified to any of a variety ofpromoieties using conventional techniques. For example, a carboxylmoiety in a compound of Formula Ia may be replaced by or modified to acorresponding amides, carbamates, carbonates, or esters, provided thatbiotransformation processes can yield the appropriate carboxyl form ofthe parent compound. Ideally the prodrug form will, uponbiotransformation, yield the parent compound in a high recovery ratio,and will be non-toxic or have no significant safety concerns.

Accordingly, in one aspect, there are provided compounds of Formula I inwhich the carboxyl group attached to the central thiophene of a compoundis esterified, e.g., the group C(O)OH is replaced by the groupC(O)O—R^(P), wherein R^(P) is —C₁₋₄alkyl, —C₁₋₄alkyl-OC(O)O—C₁₋₄alkyl,5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl, or —C₁₋₄alkyl-NR^(U)R^(V),wherein R^(U) and R^(V) are independently hydrogen or —C₁₋₄alkyl.

In some aspects, compounds of Formula are contemplated as describedherein wherein R⁴ is other than hydrogen.

In some embodiments, prodrug forms of a compound of Formula I can havereduced potency for inhibition of HCV polymerase. Alternatively, suchprodrug forms can have an IC₅₀ against HCV polymerase that is at least50-fold, at least 100-fold, at least 150-fold, at least 200-fold, or atleast 500-fold higher than the IC₅₀ of the corresponding unmodifiedcarboxyl form of the compound.

General Preparation of Compounds

The compounds of the invention may be prepared by any suitable syntheticroute, using chemical techniques and apparatus known to the skilledorganic chemist. Details of the syntheses of exemplary compounds areprovided in the Examples below. General outlines of such syntheticprocesses are provided to aid the understanding of the invention.

General Scheme 1 shows a preparation of compounds within Formula I.Commercially available methyl 3-aminothiophene-2-carboxylate 1 can betransformed into methyl 3-iodothiophene-2-carboxylate 2 by the Sandmeyerreaction [see Hodgson H. H., Chem. Rev. 1947, 40(2):251-77], such assequential treatment with tert-butyl nitrite and diiodomethane. A Suzukireaction [see Suzuki, A. J. Organometallic Chem. 1999, 576:147-68] of 2with pyridineboronic acid 3 affords 4. Palladium catalyzed coupling of 4with an organo-metallic compound 5 (such as alkylzinc, or alkenylboronicacid) results in 6. Alkylation of pyridine in 6 is achieved by stirringwith an alkyl halide, such as an alkyl iodide or alkyl bromide, in aninert solvent (such as acetonitrile). Reduction of 7 is effected bysodium borohydride in methanol to give the tetrahydropyridine 8.Deprotonation of 8 with a strong base (such as LDA) in THF at lowtemperature (−78 to −40° C.) is followed by addition of iodine to give9. Suzuki coupling of 9 with a boronic acid gives 10, which issaponified to give final compound 10a. Alternatively, Sonogashiracoupling [see Chinchilla R. and Nájera C., Chem. Rev. 2007,107(3):874-922] of 9 with an alkyne results in 11, which is furthersaponified to yield final compound 11a. Suitable substitution ofappropriate pyridineboronic acids can be used to prepare compounds ofFormula I in which the nitrogen of the final tetrahydropyridine appearsin the alternative position, i.e., X═—CH— and Y═—N—.

General Scheme 2 shows an alternative preparation of compound 6 inScheme 1, when R² is a cyclic alkyl group. Treatment of a cyclic ketone12 with a strong base such as LDA at low temperature (such as 0° C. to−70° C.), then quenched with N,N-bis(trifluoromethanesulfonyl)-anilineresults in 13. Palladium-catalyzed reaction of 13 with a diboronateresults in the desired cyclic alkenylboronic acid 5a. Suzuki coupling of5a with 4 gives 6a. The cyclic alkene can be saturated with hydrogen gasunder 50 psi, to give the cyclic alkane 6b.

Alternatively, R¹ in compounds of formula 10 and 11 (General Scheme 1)can be prepared according to General Scheme 3. Compound 14 (e.g., acompound of Formula I in which R¹=benzyl) is treated with 1-chloroethylchloroformate [see Gubert et al., Synthesis, 1991, 22(44):318], to givethe cyclic secondary amine 15. The secondary amine 15 may be furtherderivatized with reductive amination, reaction with an acylchloride,reaction with a sulfonyl chloride, reaction with a chloroformate, orreaction with a carbamoyl chloride, followed by hydrolysis of thecorresponding ester to give, respectively, final compound 16a, or 16b,or 16c, or 16d, or 16e.

In General Scheme 3, R^(D) is hydrogen, —C₀₋₂alkyl,—C₀₋₂alkyl-C₃₋₆cycloalkyl, —C₁₋₃hydroxyalkyl, or —C₀₋₃alkyl-C₆₋₁₀aryl;and R^(E) is hydrogen, or —C₁₋₄alkyl; or R^(D) and R^(E) together withthe nitrogen to which they are attached can form a 4- to 6-memberedring.

In General Scheme 4, compound 3 prepared (from General Scheme 1) can bereacted with R^(2B)X, where R^(2B) is a cycloalkenyl and X is triflate(OTO or iodide (I), under Suzuki reaction conditions. The resultingpyridinyl bromide 17 can be converted to boronic acid derivative 18 viaeither a Suzuki reaction with a diboronate compound or a sequentialtreatment with butyllithium and a trialkylborate. Suzuki reactionbetween the boronic acid derivative 18 and iodide 2 from Scheme 1produces 19. Optionally, 19 with cycloalkenyl R^(2B) can be converted to20 with cycloalkanyl R^(2B) via hydrogenation under moderate pressure.Methylation of pyridine can be followed by reduction with reagent suchas sodium borohydride to give the tetrahydropyridine 22. Deprotonationof 22 by a base such as LDA is followed by quenching the anion withiodine to give 23. “N”-demethylation of 23 can be accomplished withknown methods (Wuts, P. G. M.; Greene, T. W., 2007, Greene's ProtectiveGroups in Organic Synthesis, 4^(th) Ed. Hoboken, N.J.:Wiley-Interscience) to give 24. Installation of R^(1B) on 24 to yield 25can be achieved with many methods, such as reductive amination ofketones and aldehydes, acylation with acid chloride and chloroformates,sulfonylation with sulfonyl chlorides, alkylation with alkyl halides,etc. Compound 25 can be converted via a palladium catalyzed reactionsuch as a Suzuki reaction, Negishi reaction, Sonogashira reaction, Heckreaction, Stille reaction, or Buchwald-Hartwitz amination to 26.Saponification of 26 provides the acid 27.

It will be appreciated that the compounds of Formula I may contain oneor more asymmetric carbon atoms and may exist in racemic,diastereomeric, and optically active forms. All of these racemiccompounds, enantiomers, and diastereomers are contemplated to be withinthe scope of the present invention. Methods are known in the art forseparating isomers such as enantiomers and diastereomers, includingphysical and chemical methods. It will further be appreciated thatcertain compounds of the present invention may exist in differenttautomeric forms. All tautomers are contemplated to be within the scopeof the present invention.

Certain compounds of the present invention may occur as atropisomers,which are stereoisomers that exhibit hindered rotation about a singlebond, in which the steric interconversion barrier to such rotation ishigh enough to permit isolation of individual conformers. Atropisomersmay be equilibrated thermally, and the interconversion barrier may bemeasured kinetically.

The present invention also includes isotopically-labeled compounds ofFormula I. The isotopically-labeled compounds are identical to thecompounds of this invention, but for being manufactured to replace oneor more atoms with another isotope of the same element. For example, aselected atom may be changed from a naturally abundant isotope to a rareisotope. Exemplary isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,sulfur, chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵O, ¹⁷O, ³⁵S,¹⁸F, ³⁶Cl. Certain isotope-labeled compounds (e.g., ³H and ¹⁴C) areuseful in compound or substrate tissue distribution studies. Certainheavier isotopes (e.g., ²H) may afford therapeutic advantages resultingfrom possible greater metabolic stability.

Also included within the present invention are salts, (e.g.,pharmaceutically acceptable salts) of the compounds of Formula I, andparticularly compounds of Formula Ia. Any salt that is consistent withthe overall stability and utility of the compounds of Formula I may beprovided using conventional methods. Suitable salts include, withoutlimitation, salts of acidic or basic groups that can be present in thecompounds provided herein. Under certain acidic conditions, the compoundcan form a wide variety of salts with various inorganic and organicacids. Acids that can be used to prepare pharmaceutically acceptablesalts of such basic compounds are those that form salts comprisingpharmacologically acceptable anions including, but not limited to,acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide,calcium edetate, camsylate, carbonate, chloride, bromide, iodide,citrate, dihydrochloride, edetate, edisylate, estolate, esylate,fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrabamine, hydroxynaphthoate, isethionate, lactate,lactobionate, malate, maleate, mandelate, mesylate (methylenesulfonate),methylsulfate, muscate, napsylate, nitrate, panthothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate,succinate, sulfate, tannate, tartrate, teoclate, triethiodide andpamoate. Under certain basic conditions, the compound can form basesalts with various pharmacologically acceptable cations. Non-limitingexamples of such salts include alkali metal or alkaline earth metalsalts and, particularly, calcium, magnesium, sodium, lithium, zinc,potassium and iron salts, as well as tetraalkylammonium salts. Generalinformation regarding pharmaceutically acceptable salts may be found inStahl P H, and Wermuth C G, eds., Handbook of Pharmaceutical Salts:Properties, Selection and Use, 2002, Wiley-VCH/VHCA Weinheim/Zürich.

The present invention also relates provides hydrates and other solvatesof the compounds of Formula I. Thus, hydrates and other solvates of thecompounds of Formula I and hydrates and other solvates of the salts ofthe compounds of Formula I are included within the scope of the presentinvention.

Esters, including pharmaceutically acceptable esters, of the compoundsof Formula (I) are included within the scope of the present invention.Esters include stable carboxylic acid esters —COOR, for example, inwhich R is selected from optionally substituted straight or branchedchain alkyl, alkoxyalkyl, aralkyl, aryloxyalkyl, aryl; or for example,—CH₂OC(O)R′ or —CH₂OCO₂R′ in which R′ is alkyl (e.g., R′ is tert-butyl).Unless otherwise specified, any alkyl moiety present in such esterssuitably contains 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

If there should be, in this specification, a discrepancy between adepicted structure and a name given to that structure, the depictedstructure is to be accorded more weight. In addition, if thestereochemistry of a structure or a portion of a structure is notindicated with conventionally accepted notation, for example, bold ordashed lines, the structure or portion thereof is to be interpreted asencompassing all stereoisomers of such structure.

A compound of Formula I and its salts (e.g., pharmaceutically acceptablesalts) may exist in crystalline forms, which may appear as differentpolymorphs or pseudopolymorphs. As used herein, crystalline“polymorphism” means the ability of a crystalline compound to exist indifferent crystal structures. Polymorphism generally can occur as aresponse to changes in temperature, pressure, or both. Polymorphism canalso result from variations in the crystallization process. Polymorphscan be distinguished by various physical characteristics known in theart such as x-ray diffraction patterns, solubilities, and meltingpoints. Polymorphism may result from differences in crystal packing(packing polymorphism) or differences in packing between differentconformers of the same molecule (conformational polymorphism). As usedherein, crystalline “pseudopolymorphism” means the ability of a hydrateor solvate of a compound to exist in different crystal structures. Thepseudopolymorphs of the instant invention may exist due to differencesin crystal packing (packing pseudopolymorphism) or due to differences inpacking between different conformers of the same molecule(conformational pseudopolymorphism). The present invention comprises allpolymorphs and pseudopolymorphs of the compounds of Formula I and theirpharmaceutically acceptable salts.

A compound of Formula I and its salts or solvates may also exist asamorphous solids. As used herein, an amorphous solid is a solid in whichthere is no long-range order of the positions of the atoms in the solid.This definition applies as well when the crystal size is two nanometersor less. Additives, including solvents, may be used to create theamorphous forms of the instant invention. The instant inventioncomprises all amorphous forms of the compounds of Formula I and theirsalts, (e.g., pharmaceutically acceptable salts) and solvates.

In one aspect the invention provides a composition comprising a compoundaccording to Formula I or a salt (e.g., a pharmaceutically acceptablesalt) or solvate thereof. Such compositions may further comprise atleast one further component, such as a pharmaceutically acceptablecarrier or excipient.

Methods of Use

In another aspect, the invention provides a method for treating ahepatitis C virus infection in a host, comprising administering to thehost a therapeutic amount of at least one compound according to FormulaI, or a pharmaceutically acceptable salt thereof. There is likewiseprovided a compound according to Formula I or a pharmaceuticallyacceptable salt of such compound, for use in the treatment of a HCVinfection in a host. In some embodiments, the method further comprisesadministering to the host at least one other therapeutically activeagent selected from the group consisting of interferons, ribavirin,taribavirin, nucleoside HCV polymerase inhibitors, non-nucleoside HCVpolymerase inhibitors, HCV NS3-4A protease inhibitors, HCV NS5Ainhibitors, HCV entry inhibitors, HCV NS3 inhibitors, and HCV NS4Binhibitors. In some embodiments, the compound may be used for preventingHCV infection in a host. In some embodiments, the compound may be usedto limit infection in a host. In some embodiments, the host is a humansubject. In some embodiments, the compound is a compound of Formula Ia.In some embodiments, the HCV genotype is 1, or the HCV genotype is 1a,or the HCV genotype is 1b.

In another aspect, the invention provides a method for treating ahepatitis C virus reactivation in a host, comprising administering tothe host a therapeutic amount of at least one compound according toFormula I, or a pharmaceutically acceptable salt thereof. There islikewise provided a compound according to Formula I or apharmaceutically acceptable salt of such compound, for use in thetreatment of a HCV infection in a host. In some embodiments, the methodfurther comprises administering to the host at least one othertherapeutically active agent selected from the group consisting ofinterferons, ribavirin, taribavirin, nucleoside HCV polymeraseinhibitors, non-nucleoside HCV polymerase inhibitors, HCV NS3-4Aprotease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors, HCV NS3inhibitors, and HCV NS4B inhibitors. In some embodiments, the compoundmay be used for preventing HCV infection in a host. In some embodiments,the compound may be used to limit infection in a host. In someembodiments, the host is a human subject. In some embodiments, thecompound is a compound of Formula Ia. In some embodiments, the HCVgenotype is 1, or the HCV genotype is 1a, or the HCV genotype is 1b.

In another aspect, the invention provides a method for inhibiting orreducing the activity of hepatitis C virus polymerase in a host,comprising administering to the host a therapeutic amount of at leastone compound according to Formula I or a pharmaceutically acceptablesalt thereof. There is likewise provided a compound according to FormulaI, or a pharmaceutically acceptable salt of such compound, for use ininhibiting or reducing the activity of HCV polymerase in a host. In someembodiments, the method further comprises administering to the host atleast one other therapeutically active agent selected from the groupconsisting of interferons, ribavirin, taribavirin, nucleoside HCVpolymerase inhibitors, non-nucleoside HCV polymerase inhibitors, HCVNS3-4A protease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors,HCV NS3 inhibitors, and HCV NS4B inhibitors. In some embodiments, thehost is a human subject. In some embodiments, the compound is a compoundof Formula Ia. In some embodiments, the HCV genotype is 1, or the HCVgenotype is 1a, or the HCV genotype is 1b.

In a further aspect, the invention provides a method for inhibiting orreducing hepatitis C virus polymerase replication in a host, comprisingadministering to the host a therapeutic amount of at least one compoundaccording to Formula I or a pharmaceutically acceptable salt thereof.There is likewise provided a compound according to Formula I, or apharmaceutically acceptable salt of such compound, for use in inhibitingor reducing HCV polymerase replication in a host. In some embodiments,the method further comprises administering to the host at least oneother therapeutically active agent selected from the group consisting ofinterferons, ribavirin, taribavirin, nucleoside HCV polymeraseinhibitors, non-nucleoside HCV polymerase inhibitors, HCV NS3-4Aprotease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors, HCV NS3inhibitors, and HCV NS4B inhibitors. In some embodiments, the host is ahuman subject. In some embodiments, the compound is a compound ofFormula Ia. In some embodiments, the HCV genotype is 1, or the HCVgenotype is 1a, or the HCV genotype is 1b.

In another aspect, the invention provides a method of treatingHCV-associated liver cirrhosis, chronic liver disease, hepatocellularcarcinoma, cryoglobulinaemia, and/or liver fibrosis in a host, whichcomprises administering to the host a therapeutic amount of at least onecompound according to Formula I or a pharmaceutically acceptable saltthereof. There is likewise provided a compound according to Formula I,or a pharmaceutically acceptable salt of such compound, for use inHCV-associated liver cirrhosis, chronic liver disease, hepatocellularcarcinoma, cryoglobulinaemia, and/or liver fibrosis in a host. In someembodiments, the method further comprises administering to the host atleast one other therapeutically active agent selected from the groupconsisting of interferons, ribavirin, taribavirin, nucleoside HCVpolymerase inhibitors, non-nucleoside HCV polymerase inhibitors, HCVNS3-4A protease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors,HCV NS3 inhibitors, and HCV NS4B inhibitors. In some embodiments, thehost is a human subject. In some embodiments, the compound is a compoundof Formula Ia. In some embodiments, the HCV genotype is 1, or the HCVgenotype is 1a, or the HCV genotype is 1b.

In another aspect, the invention provides a use of a compound accordingto Formula I or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for treating a hepatitis C virus infectionin a host. In some embodiments, the host is a human subject. In someembodiments, the compound is a compound of Formula Ia. In someembodiments, the HCV genotype is 1, or the HCV genotype is 1a, or theHCV genotype is 1b.

In another aspect, the invention provides a use of a compound accordingto Formula I or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for inhibiting or reducing the activity ofhepatitis C virus polymerase in a host. In some embodiments, the host isa human subject. In some embodiments, the compound is a compound ofFormula Ia. In some embodiments, the HCV genotype is 1, or the HCVgenotype is 1a, or the HCV genotype is 1b.

In another aspect, the invention provides a use of a compound accordingto Formula I or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for inhibiting or reducing hepatitis C viruspolymerase replication in a host. In some embodiments, the host is ahuman subject. In some embodiments, the compound is a compound ofFormula Ia. In some embodiments, the HCV genotype is 1, or the HCVgenotype is 1a, or the HCV genotype is 1b.

The invention provides, in a further aspect, a combination comprising atleast one compound of Formula I or a pharmaceutically acceptable saltthereof together with at least one other active agent, especiallyinterferon, ribavirin, and/or an additional anti-HCV agent. In someembodiments, the compound is a compound of Formula Ia. In someembodiments, the HCV genotype is 1, or the HCV genotype is 1 a, or theHCV genotype is 1b.

In a further aspect of the present invention there is provided acompound chosen from compounds of Formula I or a pharmaceuticallyacceptable salt thereof for use in human or veterinary medical therapy,particularly in the treatment or prevention of viral infection,particularly flavivirus infection, for example, HCV infection. In someembodiments, the compound is a compound of Formula Ia. In someembodiments, the HCV genotype is 1, or the HCV genotype is 1a, or theHCV genotype is 1b.

In another aspect, the invention provides for the use of a compound ofFormula I or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment and/or prophylaxis ofviral infection, particularly HCV infection. In some embodiments, thecompound is a compound of Formula Ia. In some embodiments, the HCVgenotype is 1, or the HCV genotype is 1 a, or the HCV genotype is 1b.

In yet another aspect, the invention provides methods for inhibiting HCVpolymerase activity in a biological sample, comprising contacting thebiological sample with an effective inhibitory amount of a compound ofFormula I or a pharmaceutically acceptable salt thereof. In someembodiments, the biological sample is a blood, tissue, or other fluidsample. In some embodiments, the biological sample is a culture of hostcells, e.g., hepatocytes, or hepatocellular carcinoma cells, infectedwith HCV. For a survey of biological assay systems in which thecompounds of the invention may be demonstrated, see, Huang et al.,“Hepatitis C Virus-related Assays,” Chapter 2 in Hepatitis C: AntiviralDrug Discovery and Development, S-L Tan and Y He, eds., Caister AcademicPress (2011).

Such methods may be useful in research or in the clinic, for example, inthe identification of HCV genotypes amenable to inhibition with thecompounds of the invention or the identification of subjects who maybeneficially be treated using compounds or compositions of theinvention. In some embodiments, the compound is a compound of FormulaIa. In some embodiments, the HCV genotype is 1, or the HCV genotype is1a, or the HCV genotype is 1b.

In various of the embodiments of the methods, set forth above, of usingthe compounds of the invention for treatment or prevention of HCVinfection or the sequelae of such infection, the HCV may begenotypically unidentified. In other embodiments, the HCV is HCVgenotype 1, optionally HCV genotype 1 a or 1b. In other embodiments, theHCV may be selected from among other HCV genotypes, including HCVgenotypes 2 and/or 3.

Without intending to be bound by theory, it is believed that thecompounds of Formula I that exhibit inhibition of HCV replication orinfectivity derive their activity through interaction with or binding toan allosteric site controlling the conformation of the HCV NS5B protein,and thereby inhibiting viral RNA synthesis in the host cell. It isbelieved that the compounds of Formula I that exhibit inhibition of HCVreplication or infectivity interact with or bind to the NNI IIallosteric site. As demonstrated in the Examples below, compounds ofFormula I exhibit potent inhibition of the NS5B RdRp activity in abiochemical assay in vitro as well as inhibition of HCV replication asmeasured in an HCV replicon cell assay.

Definitions

It is understood that the compounds of the invention, as describedherein, may be substituted with a variety of substituents or functionalmoieties. In general, the term “substituted,” whether or not preceded bythe term “optionally,” and substituents contained in formulas of thisinvention, refer to the replacement of hydrogen radicals in a givenstructure with the radical of a specified substituent. When more thanone position in any given structure may be substituted with more thanone substituent selected from a specified group, the substituents are,unless otherwise indicated, to be understood as independent, i.e., theymay be either the same or different at every position. As used herein,the term “substituted” is contemplated to include all permissiblesubstituents of organic compounds. In a broad aspect, the permissiblesubstituents include acyclic and cyclic, branched and unbranched,carbocyclic and heterocyclic, aromatic and non-aromatic, carbon andheteroatom substituents of organic compounds. For purposes of thisinvention, heteroatoms such as nitrogen may have hydrogen substituentsand/or any permissible substituents of organic compounds describedherein which satisfy the valencies of the heteroatoms. Furthermore, thisinvention is not intended to be limited in any manner by the permissiblesubstituents of organic compounds. Combinations of substituents andvariables envisioned by this invention are preferably those that resultin the formation of stable compounds useful as described herein, forexample, in the treatment and prevention of disorders associated withHCV infection.

The term “aliphatic,” as used herein, includes both saturated andunsaturated, straight chain (i.e., unbranched) or branched aliphatichydrocarbons, which are optionally substituted with one or morefunctional groups. As will be appreciated by one of ordinary skill inthe art, “aliphatic” is intended herein to include, but is not limitedto, alkyl, alkenyl, alkynyl moieties. Thus, as used herein, the term“alkyl” includes straight and branched alkyl groups. An analogousconvention applies to other generic terms such as “alkenyl,” “alkynyl”and the like. Furthermore, as used herein, the terms “alkyl,” “alkenyl,”“alkynyl,” and the like encompass both substituted and unsubstitutedgroups.

In certain embodiments, the alkyl, alkenyl and alkynyl groups employedin the invention contain about 1-20 aliphatic carbon atoms (C₁₋₂₀). Incertain other embodiments, the alkyl, alkenyl, and alkynyl groupsemployed in the invention contain about 1-10 aliphatic carbon atoms(C₁₋₁₀). In yet other embodiments, the alkyl, alkenyl, and alkynylgroups employed in the invention contain about 1-8 aliphatic carbonatoms (C₁₋₈). In still other embodiments, the alkyl, alkenyl, andalkynyl groups employed in the invention contain about 1-6 aliphaticcarbon atoms (C₁₋₆). In yet other embodiments, the alkyl, alkenyl, andalkynyl groups employed in the invention contain about 1-4 carbon atoms(C₁₋₄). Aliphatic groups include, for example, for example, methyl,ethyl, n-propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl,sec-hexyl, and the like, which may bear one or more substituents.Alkenyl groups include, for example, ethenyl, propenyl, butenyl,1-methyl-2-buten-1-yl, and the like. Alkynyl groups include, forexample, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.

The term “alkoxy,” as used herein, refers to a group having the formula—OR wherein R is C₁₋₆alkyl or C₁₋₆haloalkyl. Such groups includemethoxy, ethoxy, propoxy, and the like. In some embodiments, an alkoxygroup may be a C₁₋₃alkoxy group, optionally substituted with 1-3halogens. In some embodiments, an alkoxy group may be a C₁₋₄alkoxygroup, optionally substituted with 1-5 halogens. When substituted withone or more halogens, alkoxy groups may be referred to a “haloalkoxy”groups.

The term “alkyl,” as used herein, refers to a saturated straight chainor branched hydrocarbon. In some embodiments, alkyl groups have 1 to 10(C₁₋₁₀), 1 to 6 (C₁₋₆), or 1 to 3 (C₁₋₃) carbon atoms. Representativesaturated straight chain alkyl substituents include methyl, ethyl,n-propyl, n-butyl, n-pentyl, and n-hexyl; while saturated branched alkylsubstituents include isopropyl, sec-butyl, isobutyl, tert-butyl,isopentyl, 2-methylbutyl, 3-methylbutyl, and the like.

The terms “amine” and “amino,” as used herein, refer to a group havingthe formula —NR′R″ wherein R′ and R″ are both hydrogen. The term“alkylamine,” as used herein, refers to a group having the formula—NR′R″ wherein R′ is hydrogen or alkyl, and R″ is alkyl. Thus, the termalkylamine includes monoalkylamine and dialkylamine.

The term “IC₅₀,” as used herein, refers to an amount, concentration, ordosage of a particular test compound that achieves a 50% inhibition of amaximal response in an in vitro assay—such as a biochemical or enzymaticassay—that measures such response.

The term “aralkyl,” as used herein refers to a group of the formula-RaRb where Ra is an alkyl group as defined above, substituted by Rb, anaryl group, as defined above, e.g., benzyl.

The term “aryl,” as used herein, refers to a group of carbocylic ringsystem, including monocyclic, bicyclic, tricyclic, tetracyclic 3- to14-membered carbocyclic (C₃₋₁₄) ring systems, wherein at least one ofthe rings is an aromatic moiety, any of which may optionally besubstituted. The aryl moiety may be fully aromatic, examples of whichare phenyl, naphthyl, anthracenyl, acenaphthylenyl, azulenyl, fluorenyl,indenyl, indolyl, indazolyl, triazolopyrmidinyl, and pyrenyl. The arylgroup may also contain an aromatic ring in combination with anon-aromatic ring, examples of which are acenaphene, indene, andfluorene. In certain embodiments of the present invention, “aryl” refersto a mono- or bicyclic carbocyclic ring system having one or two ringssatisfying the Huckel rule for aromaticity, including, but not limitedto, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, phenanthryl,anthracyl, and the like.

The term “cycloalkyl,” as used herein, refers specifically to monocyclicor bicyclic alkyl groups having three to seven, preferably three to tencarbon atoms. Suitable cycloalkyl moieties include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, whichmay optionally be substituted.

The term “halogen,” as used herein, refers to F, Cl, Br, or I.

The term “haloalkyl,” as used herein, refers to an alkyl group, such asa —C₁₋₆alkyl group, in which one or more of the hydrogen atoms isreplaced by a halogen. Such groups include chloromethyl, fluoromethyl,trifluoromethyl, and the like. In some embodiments, a haloalkyl groupmay be a —C₁₋₃alkyl group substituted with 1-3 halogens. In someembodiments, a haloalkyl group may be a —C₁₋₄alkyl group substitutedwith 1-5 halogens. The term “HCV polymerase,” as used herein, refers tothe NS5B polymerase of HCV.

The term “heteroaryl,” as used herein, refers to a stable 3- to15-membered aromatic ring moiety that consists of carbon atoms and fromone to five heteroatoms independently selected from N, O, and S, and mayoptionally be substituted. In some embodiments, the heteroaryl moietymay be a monocyclic, bicyclic, tricyclic, or tetracyclic ring; andnitrogen or sulfur atoms in the ring structure may be optionallyoxidized; and nitrogen atom(s) may be optionally quaternized. Theheteroaryl moiety ring may be attached to the main structure at anyheteroatom or carbon atom that results in the creation of a stablecompound. Exemplary heteroaryl groups include pyridyl, pyrazinyl,pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,isoquinolinyl, pyrazolopyrimidinyl, furopyridinyl, and the like.

The term “heterocyclyl,” as used herein, refers to a stable 3- to15-membered aromatic or non-aromatic ring moiety that consists of carbonatoms and from one to five heteroatoms independently selected from N, O,and S, and may optionally be substituted. In some embodiments, theheterocyclic group may be a monocyclic, bicyclic, tricyclic, ortetracyclic group, which may include fused or bridged rings; and thenitrogen or sulfur atoms in the heterocyclic group may be optionallyoxidized; the nitrogen atom may be optionally quaternized; and theheterocyclic group may be aromatic, or partially or fully saturated. Theheterocyclic group may be attached to the main structure at anyheteroatom or carbon atom that results in the creation of a stablecompound. Exemplary heterocyclic groups include heteroaryl groups asdescribed herein and non-aromatic heterocyclic groups, i.e.,heterocycloalkyl groups, such as morpholinyl, piperidinyl, piperazinyl,pyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,tetrahydropyranyl, dioxolanyl, and the like.

The term “pharmaceutically acceptable,” as used herein in relation to aningredient (such as an active ingredient, a salt thereof, or anexcipient) that may be included in a pharmaceutical formulation foradministration to a patient, refers to that ingredient being acceptablein the sense of being compatible with any other ingredients present inthe pharmaceutical formulation and not being deleterious to the patient.

The term “preventing,” as used herein, means that the compounds of thepresent invention are useful when administered to a patient who has notbeen diagnosed as possibly having the disease at the time ofadministration, but who would normally be expected to develop thedisease or be at increased risk for the disease. Generally, the term“preventing” refers to administration of a compound of the inventionprior to the onset of symptoms, particularly to patients at risk ofcontracting HCV infection. The compounds of the invention will slow thedevelopment of disease symptoms, delay the onset of disease, or preventthe individual from developing the disease at all.

The term “prodrug,” as used herein, refers to a chemical compound thathas little or no pharmacological activity per se or that has propertiesthat are preferred for administration, but that is capable of undergoingbiotransformation to a therapeutically active metabolite of interest.For example, a prodrug form of a compound of Formula I may itself havelittle or no inhibitory activity against HCV polymerase, but wouldundergo biotransformation in the body of the patient to the active formof the compound. As another example, a prodrug form of a compound ofFormula I may have one or more physicochemical properties, e.g.,solubility, that imparts to the compound a different pharmacokinetic orpharmacodynamic profile. Biotransformation can include hydrolysis,oxidation, photolysis, or by means of physiological or metabolicprocesses, e.g., by enzymatic modification. A prodrug may be thought ofas including the therapeutic compound covalently linked to a promoiety,and the biotransformation process removes or modifies the promoiety toyield the therapeutic compound. Common functional groups on compoundsthat may be replaced with or modified to contain a promoiety include,for example, amino, carbonyl, carboxyl, hydroxyl, phosphoryl, andthiolyl groups. See, e.g., Rautio et al., Nat Rev Drug Discov, 2008,7:255-270. If a parent drug contains one of these moieties, the compoundmay be modified using bioreversible chemistry to contain a promoiety.Alternatively, the prodrug may be prepared with the promoietyincorporated at an earlier synthetic stage, as may be desired.

The term “solvate,” as used herein, refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound ofFormula I or a salt thereof) and a solvent. Such solvents for thepurpose of the invention may not interfere with the biological activityof the solute. Examples of suitable solvents include, but are notlimited to, water, methanol, ethanol and acetic acid. Preferably thesolvent used is a pharmaceutically acceptable solvent. However, solvateshaving non-pharmaceutically acceptable solvents are within the scope ofthe present invention, for example, for use as intermediates in thepreparation of other compounds of Formula I and their pharmaceuticallyacceptable salts. Most preferably the solvent used is water and theresulting solvate may also be referred to as a hydrate. As used hereinand unless otherwise indicated, the term “hydrate” means a compoundprovided herein or a salt thereof that further includes a stoichiometricor nonstoichiometric amount of water bound by non-covalentintermolecular forces.

The term “stable,” as used herein, refers to compounds that possessstability sufficient to allow their manufacture, and that maintain theintegrity of the compound for a sufficient period of time to be detectedand preferably for a sufficient period of time to be useful for thepurposes detailed herein. For example, a compound of the inventionshould be sufficiently stable to permit its purification, or isolation,or identification; or should be sufficiently stable to permitformulation into a pharmaceutically acceptable dosage form.

The term “subject,” as used herein, is an animal, typically a mammal,most typically a human, such as a patient. The term “host,” as usedherein, is a cell, such as a hepatocyte, or a human patient or othersubject suspected of being, or determined to have been, infected withHCV, as determined through conventional genetic or serologic techniques.

The term “substituted,” as used herein, refers to a moiety in which atleast one hydrogen atom is replaced by a non-hydrogen substituent. Forexample if a phenyl group is said to be optionally substituted, at leastone of the hydrogens in the phenyl ring is replaced with a substituentthat is not hydrogen. Typically, such substituents are small moieties,such as halo, hydroxyl, C₁₋₄alkyl, C₁₋₄alkoxy, or cyano. Suchsubstitutions generally either contribute to a desirable property forthe molecule or at least do not substantially detract from the desirableproperties of the molecule, and in any case should be sufficientlystable for use according to the purposes set forth herein.

The term “therapeutic amount,” as used herein, refers to an amount of acompound that would be reasonably expected by the skilled medicalpractitioner to have a particular therapeutic effect in the patient,taking into consideration such factors as the sex, age, geneticbackground, body mass, body surface area, mode of administration, andthe like, notwithstanding idiosyncrasies of the patient's physiology.The therapeutic effect may be realized in the treatment, prevention,and/or management of a HCV infection or a condition or symptomassociated with such infection, or the delay or minimization of one ormore symptoms associated therewith. The term “therapeutic amount” cantherefore, encompass an amount that improves overall therapy, reduces oravoids symptoms or causes of HCV infection, or enhances the therapeuticefficacy of another therapeutic agent. It is possible that a therapeuticamount of a compound may achieve different results when administered todifferent patients. In some cases, an amount of a compound that producestherapeutic benefit to one patient may yield little or no benefit foranother patient, but is still considered a therapeutic amount. In someembodiments, a therapeutic amount of an active compound is an amountdetermined by the US Food and Drug Administration (or a correlativeorganization in another country or region) to be safe and effective inthe treatment of HCV infection or another specified disease or disorderin a human patient.

It will be appreciated that reference herein to “therapy” and/or“treatment” includes, but is not limited to prevention, retardation,prophylaxis, amelioration, and/or cure of the HCV infection orconsequent or associate medical symptoms, conditions, or other sequelae.It will thus be appreciated that references herein to treatment orprevention of HCV infection include treatment or prevention of chronicHCV infection, acute HCV infection, or any of the HCV-associateddiseases and disorders such as liver fibrosis, hepatic steatosis,cirrhosis, cryoglobulinemia, and hepatocellular carcinoma. Accordingly,the terms “treat,” “treating,” and “treatment,” as used herein refer toalleviating or reducing the severity of a symptom associated with HCVinfection or a condition consequent to such infection. In certainembodiments, compounds of the invention will delay or slow theprogression of HCV infection, or a condition consequent to suchinfection, thereby making it possible for the subject to enjoy a longerlife span or a better quality of life.

The term “subtherapeutic amount,” as used herein, refers to an amount ofa compound that, if administered alone, would be expected to exhibit notherapeutic effect or no significant therapeutic effect in the patient,taking into consideration the foregoing factors. Subtherapeutic amountsof a compound of Formula I may be useful in combination therapy, inwhich, for example, two or more active compounds are administered toachieve a therapeutic effect.

Therapeutic or treatment effect may be measured in any manner known inthe art. Therapeutic effect may be observed in asymptomatic HCV patientsby way of delaying, reducing, or preventing onset or development of oneor more such symptoms characteristic of HCV disease. For example,therapeutic effect may be observed through delay, reduction, orprevention of a liver pathology. As another example, therapeutic effectmay be observed through reduction of viral load (such as by qPCRassessment of the number of copies of HCV RNA in a patient's blood).See, e.g., Highleyman L. and Franciscus A., “HCV Diagnostic Tools: HCVViral Load Tests,” HCSP Fact Sheet, v.3 May 2011[http://www.hcvadvocate.org/hepatitis/factsheets_pdf/viralload.pdf].

The term “effective amount,” as used herein, refers to an amount of acompound that, when provided to a host cell or an in vitro or ex vivosystem would be expected to exhibit an overt or measurable effect in thesystem. For example, in an acellular or cellular assay system suitablefor measuring an activity of HCV polymerase, the compounds of Formula Imay inhibit or reduce such activity of HCV polymerase when provided inan effective amount. As another example, in an cellular assay systemsuitable for measuring replication or infectivity of HCV, the compoundsof Formula I may inhibit or reduce such activity of HCV when provided inan effective amount.

Pharmaceutical Compositions and Dosage Forms

The invention provides compositions, and in particular, pharmaceuticalcompositions, comprising any of the compounds of Formula I (e.g., asingle enantiomer, a mixture of enantiomers, or a mixture ofdiastereomers thereof, or a pharmaceutically acceptable salt or solvatethereof) in combination with a pharmaceutically acceptable vehicle,carrier, diluent, excipient, or a mixture of one or more of theforegoing ingredients.

While numerous embodiments of compositions according to the inventionare set forth in detail below, it will be understood by the skilledperson that compounds of Formula I are not limited to use incompositions specifically adapted for administration as medicaments, butthat many other compositions comprising any of the compounds of FormulaI may be made using conventional materials and methods. Accordingly, theinvention provides compositions comprising any of the compounds ofFormula I (e.g., a single enantiomer, a mixture of enantiomers, or amixture of diastereomers thereof, or a salt or solvate thereof) incombination with at least one vehicle, carrier, diluent, excipient, or amixture of one or more of the foregoing ingredients. For example, it isto be expected that any of the compounds of Formula I may appear insolution with a solvent that is considered not acceptable foradministration to humans or other subjects. In addition, any of thecompounds of Formula I may be prepared as a salt of a compound that isconsidered not acceptable for administration to humans or othersubjects. The skilled person will understand how to prepare andinterconvert such salt forms of the compounds, and such compositionscomprising such compounds, by way of conventional techniques.

The amounts of various compounds of Formula I to be administered can bedetermined by standard procedures taking into account factors such asthe compound (IC₅₀) potency, (EC₅₀) efficacy, and the biologicalhalf-life (of the compound), the age, size and weight of the patient,and the disease or disorder associated with the patient. The importanceof these and other factors to be considered are known to those ofordinary skill in the art.

Amounts administered also depend on the routes of administration and thedegree of oral bioavailability. For example, for compounds of Formula Iwith low oral bioavailability, relatively higher doses will have to beadministered. Oral administration is a convenient method ofadministration of the compounds of Formula I.

Suitably the pharmaceutical composition is in unit dosage form. For oraladministration, for example, a tablet or capsule may be administered;for nasal application, a metered aerosol dose may be administered; fortransdermal application, a topical formulation or patch may beadministered; and for transmucosal delivery, a buccal patch may beadministered.

Each dosage unit for oral administration may contain from 0.01 to 500mg/Kg, for example from 0.1 to 50 mg/Kg, of a compound of Formula I- ora pharmaceutically acceptable salt thereof, calculated as the free base.The daily dosage for parenteral, nasal, oral inhalation, transmucosal,or transdermal routes may contains from 0.01 mg to 100 mg/Kg, of acompound of Formula (I). A topical formulation may contain 0.01 to 5.0%of a compound of Formula I. The active ingredient may be administeredfrom 1 to 4 times per day, for example once, twice or three times perday, sufficient to achieve the desired pharmaceutical activity.

The pharmaceutical compositions may be formulated in various dosageforms, including, but not limited to, the dosage forms for oral,parenteral, or topical administration. The pharmaceutical compositionsmay also be formulated as modified release dosage forms, including, butnot limited to, delayed, extended, prolonged, sustained, pulsatile,controlled, accelerated, fast, targeted, and programmed release, andgastric retention dosage forms. These dosage forms can be preparedaccording to conventional methods and techniques known to those skilledin the art. See, e.g., Remington: The Science and Practice of Pharmacy,21^(st) ed., 2005, Lippincott Williams & Wilkins; Ansel's PharmaceuticalDosage Forms and Drug Delivery Systems, 9^(th) ed., 2010, LippincottWilliams & Wilkins.

In one aspect of the invention, the pharmaceutical compositions areprovided in a dosage form for oral administration, which comprise acompound provided herein, including a single enantiomer, a mixture ofenantiomers, or a mixture of diastereomers thereof, or apharmaceutically acceptable salt, solvate; and a pharmaceuticallyacceptable vehicle, carrier, diluent, excipient, or a mixture thereof.

In another aspect of the invention, the pharmaceutical compositions areprovided in a dosage form for parenteral administration, which comprisea compound provided herein, including a single enantiomer, a mixture ofenantiomers, or a mixture of diastereomers thereof, or apharmaceutically acceptable salt, solvate; and a pharmaceuticallyacceptable vehicle, carrier, diluent, excipient, or a mixture thereof.

In yet another aspect of the invention, the pharmaceutical compositionsare provided in a dosage form for topical administration, which comprisea compound provided herein, including a single enantiomer, a mixture ofenantiomers, or a mixture of diastereomers thereof, or apharmaceutically acceptable salt, solvate; and a pharmaceuticallyacceptable vehicle, carrier, diluent, excipient, or a mixture thereof.

The pharmaceutical compositions provided herein may be provided in aunit- or multiple-dosage form. A unit-dosage form, as used herein,refers to a physically discrete unit suitable for administration to asubject, and packaged individually as is known in the art. Eachunit-dose contains a predetermined quantity of the active ingredient(s)sufficient to produce the desired therapeutic effect, in associationwith the required pharmaceutically acceptable vehicle, carrier, diluent,excipient, or a mixture thereof. Examples of a unit-dosage form includean ampoule, syringe, and individually packaged tablet and capsule. Aunit-dosage form may be administered in fractions or multiples thereof.A multiple-dosage form is a plurality of identical unit-dosage formspackaged in a single container to be administered in a segregatedunit-dosage form. Examples of multiple-dosage forms include, withoutlimitation, vials, bottles, blister-packs, and cardboard packages oftablets or capsules.

The pharmaceutical compositions provided herein may be administered atonce, or multiple times at intervals of time. It is understood that thedosage and duration of treatment suitable for a particular patient mayvary with the age, weight, and condition of the patient being treated,and may be determined empirically using known testing protocols or byextrapolation from in vivo or in vitro test or diagnostic data. It isfurther understood that for any particular individual, specific dosageregimens should be adjusted over time according to the individual needand the professional judgment of the person administering or supervisingthe administration of the pharmaceutical compositions provided herein.

Oral Administration

The pharmaceutical compositions provided herein may be provided insolid, semisolid, or liquid dosage forms for oral administration. Asused herein, oral administration also includes buccal, lingual, andsublingual administration. Suitable oral dosage forms include, but arenot limited to, tablets, capsules, pills, troches, lozenges, pastilles,cachets, pellets, medicated chewing gum, granules, bulk powders,effervescent or non-effervescent powders or granules, solutions,emulsions, suspensions, wafers, sprinkles, elixirs, and syrups.

In addition to the active ingredient(s), the pharmaceutical compositionsfor oral administration may contain one or more pharmaceuticallyacceptable carriers or excipients, including, but not limited to,binders, fillers, diluents, disintegrants, wetting agents, lubricants,glidants, coloring agents, dye-migration inhibitors, sweetening agents,and flavoring agents. Suitable pharmaceutically acceptable carriers andexcipients are known and described in the art. See, e.g., R C Rowe,Handbook of Pharmaceutical Excipients, 6^(th) ed., 2009, PharmaceuticalPress.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders or fillersinclude, but are not limited to, starches, such as corn starch, potatostarch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars,such as sucrose, glucose, dextrose, molasses, and lactose; natural andsynthetic gums, such as acacia, alginic acid, alginates, extract ofIrish moss, panwar gum, ghatti gum, mucilage of isabgol (psyllium)husks, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose (EC),cellulose acetate, carboxymethyl cellulose (CMC), methyl cellulose,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, suchas AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMCCorp., Marcus Hook, Pa.); and mixtures thereof. Suitable fillersinclude, but are not limited to, talc, calcium carbonate,microcrystalline cellulose, powdered cellulose, dextrates, kaolin,mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, andmixtures thereof. In certain embodiments, the binder or filler ispresent from about 50 to about 99% by weight in the pharmaceuticalcompositions provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methyl cellulose and CMC; wood products; naturalsponge; cation exchange resins; alginic acid; gums, such as guar gum andVeegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose;cross-linked polymers, such as crospovidone; cross-linked starches;calcium carbonate; microcrystalline cellulose, such as sodium starchglycolate; polacrilin potassium; starches, such as corn starch, potatostarch, tapioca starch, and pregelatinized starch; clays; aligns; andmixtures thereof. The amount of a disintegrant in the pharmaceuticalcompositions provided herein varies upon the type of formulation, and isreadily discernible to those of ordinary skill in the art. In certainembodiments, the pharmaceutical compositions provided herein containfrom about 0.5 to about 15% or from about 1 to about 5% by weight of adisintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; sodium stearyl fumarate; mineral oil; light mineraloil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenateand polyethylene glycol (PEG); stearic acid; stearyl fumaric acid;sodium lauryl sulfate; talc; hydrogenated vegetable oil, includingpeanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, cornoil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar;starch; lycopodium; silica or silica gels, such as AEROSIL® 200 (W.R.Grace Co., Baltimore, Md.) and CAB-O-SILO (Cabot Co., Boston, Mass.);and mixtures thereof. In certain embodiments, the pharmaceuticalcompositions provided herein contain about 0.1 to about 5% by weight ofa lubricant.

Suitable glidants include, but are not limited to, colloidal silicondioxide, CAB-O-SILO, and asbestos-free talc.

Suitable coloring agents include, but are not limited to, any of theapproved, certified, water soluble FD&C dyes, water insoluble FD&C dyessuspended on alumina hydrate, and color lakes, and mixtures thereof. Acolor lake is the combination by adsorption of a water-soluble dye to ahydrous oxide of a heavy metal, resulting in an insoluble form of thedye.

Suitable flavoring agents include, but are not limited to, naturalflavors extracted from plants, such as fruits, and synthetic blends ofcompounds which produce a pleasant taste sensation, such as peppermintand methyl salicylate.

Suitable sweetening agents include, but are not limited to, sucrose,lactose, mannitol, syrups, glycerin, and artificial sweeteners, such assaccharin and aspartame.

Suitable emulsifying agents include, but are not limited to, gelatin,acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylenesorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80(TWEEN® 80), and triethanolamine oleate.

Suitable suspending and dispersing agents include, but are not limitedto, sodium CMC, pectin, tragacanth, Veegum, acacia, HPMC, and PVP.

Suitable preservatives include, but are not limited to, glycerin, estersof p-hydroxybenzoic acid (e.g., methyl- and propyl-paraben), benzoicadd, sodium benzoate and alcohol.

Suitable wetting agents include, but are not limited to, propyleneglycol monostearate, sorbitan monooleate, diethylene glycol monolaurate,and polyoxyethylene lauryl ether.

Suitable solvents include, but are not limited to, glycerin, sorbitol,ethyl alcohol, and syrup.

Suitable non-aqueous liquids utilized in emulsions include, but are notlimited to, mineral oil and cottonseed oil.

Suitable organic acids include, but are not limited to, citric andtartaric acid.

Suitable sources of carbon dioxide include, but are not limited to,sodium bicarbonate and sodium carbonate.

It should be understood that a particular carrier or excipient may servemore than one function, even within the same formulation.

The pharmaceutical compositions provided herein may be provided ascompressed tablets, tablet triturates, chewable lozenges, rapidlydissolving tablets, multiple compressed tablets, enteric coated tablets,sugar-coated tablets, or film-coated tablets. Enteric coated tablets arecompressed tablets coated with substances that resist the action ofstomach acid but dissolve or disintegrate in the intestine, thusprotecting the active ingredients from the acidic environment of thestomach. Enteric-coatings include, but are not limited to, fatty acids,fats, phenyl salicylate, waxes, shellac, ammoniated shellac, andcellulose acetate phthalates. Sugar-coated tablets are compressedtablets surrounded by a sugar coating, which may be beneficial incovering up objectionable taste or odor and in protecting the tabletsfrom oxidation. Film-coated tablets are compressed tablets that arecovered with a thin layer or film of a water-soluble material. Filmcoatings include, but are not limited to, hydroxyethyl cellulose, sodiumCMC, polyethylene glycol 4000, and cellulose acetate phthalate. Filmcoating imparts the same general characteristics as sugar coating.Multiple compressed tablets are compressed tablets made by more than onecompression cycle, including layered, press-coated, and dry-coatedtablets.

The tablet dosage forms may be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination with apharmaceutically acceptable vehicle, carrier, diluent, or excipient, ora mixture thereof; including, e.g., a binder, disintegrant,controlled-release polymer, lubricant, diluent, and/or colorant.Flavoring and sweetening agents are especially useful in the formationof chewable tablets and lozenges.

The pharmaceutical compositions provided herein may be provided as softor hard capsules, which can be made from, e.g., gelatin,methylcellulose, pullulan, starch, or calcium alginate. The hard gelatincapsule, also known as a dry-filled capsule (DFC), consists of twosections, one slipping over the other, thus completely enclosing theactive ingredient. The soft elastic capsule (SEC) is a soft, globularshell, such as a gelatin shell, which is plasticized by the addition ofglycerin, sorbitol, or a similar polyol. The soft gelatin shells maycontain a preservative to prevent the growth of microorganisms. Suitablepreservatives are those as described herein, including, but not limitedto, methyl- and propyl-parabens and sorbic acid. The liquid, semisolid,and solid dosage forms provided herein may be encapsulated in a capsuleusing conventional methods. Suitable liquid and semisolid dosage formsinclude, but are not limited to, solutions and suspensions in propylenecarbonate, vegetable oils, or triglycerides. The capsules may also becoated as known by those of skill in the art in order to modify orsustain dissolution of the active ingredient.

The pharmaceutical compositions provided herein may be provided inliquid and semisolid dosage forms, including, but not limited to,emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is atwo-phase system, in which one liquid is dispersed in the form of smallglobules throughout another liquid, which can be oil-in-water orwater-in-oil. Emulsions may include a pharmaceutically acceptablenon-aqueous liquid or solvent, emulsifying agent, and preservative.Suspensions may include a pharmaceutically acceptable suspending agentand preservative. Aqueous alcoholic solutions may include apharmaceutically acceptable acetal, such as a di(lower alkyl) acetal ofa lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and awater-miscible solvent having one or more hydroxyl groups, such aspropylene glycol and ethanol. Elixirs are clear, sweetened, andhydroalcoholic solutions. Syrups are concentrated aqueous solutions of asugar, for example, sucrose, and may also contain a preservative. For aliquid dosage form, for example, a solution in a polyethylene glycol maybe diluted with a sufficient quantity of a pharmaceutically acceptableliquid carrier, e.g., water, to be measured conveniently foradministration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing an active ingredient, e.g., a compound ofFormula I, and a dialkylated mono- or polyalkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations may further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationmay be also provided in the form of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein may be provided asnoneffervescent or effervescent granules or powders, to be reconstitutedinto a liquid dosage form. Pharmaceutically acceptable carriers andexcipients used in the non-effervescent granules or powders may includediluents, sweeteners, and wetting agents. Pharmaceutically acceptablecarriers and excipients used in the effervescent granules or powders mayinclude organic acids and a source of carbon dioxide.

The pharmaceutical compositions provided herein may be formulated asimmediate or modified release dosage forms, including delayed,sustained, pulsed, controlled, targeted, and programmed release forms.

The pharmaceutical compositions provided herein may be co-formulatedwith other active ingredients which do not impair the desiredtherapeutic action, or with substances that supplement the desiredaction.

Parenteral Administration

The pharmaceutical compositions provided herein may be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, and subcutaneous administration.

The pharmaceutical compositions provided herein may be formulated in anydosage forms that are suitable for parenteral administration, includingsolutions, suspensions, emulsions, micelles, liposomes, microspheres,nanosystems, and solid forms suitable for solutions or suspensions inliquid prior to injection. Such dosage forms can be prepared accordingto conventional methods known to those skilled in the art ofpharmaceutical science. See, e.g., Remington: The Science and Practiceof Pharmacy, supra; Handbook of Pharmaceutical Excipients; supra.

The pharmaceutical compositions intended for parenteral administrationmay include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents

or preservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases. Suitable pharmaceutically acceptable carriers andexcipients are known and described in the art. See, e.g., Handbook ofPharmaceutical Excipients, supra.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringer's injection, isotonic dextrose injection,sterile water injection, and dextrose and lactated Ringer's injection.Non-aqueous vehicles include, but are not limited to, fixed oils ofvegetable origin, castor oil, corn oil, cottonseed oil, olive oil,peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, medium-chaintriglycerides of coconut oil, and palm seed oil. Water-miscible vehiclesinclude, but are not limited to, ethanol, 1,3-butanediol, liquidpolyethylene glycol (e.g., polyethylene glycol 300 and polyethyleneglycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone,N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl-and propyl-parabens, and sorbic acid. Suitable isotonic agents include,but are not limited to, sodium chloride, glycerin, and dextrose.Suitable buffering agents include, but are not limited to, phosphate andcitrate. Suitable antioxidants are those as described herein, includingbisulfite and sodium metabisulfite. Suitable local anesthetics include,but are not limited to, procaine hydrochloride. Suitable suspending anddispersing agents are those as described herein, including sodium CMC,HPMC, and PVP. Suitable emulsifying agents include those describedherein, including polyoxyethylene sorbitan monolaurate, polyoxyethylenesorbitan monooleate 80, and triethanolamine oleate. Suitablesequestering or chelating agents include, but are not limited to, EDTA.Suitable pH adjusting agents include, but are not limited to, sodiumhydroxide, hydrochloric acid, citric acid, and lactic acid. Suitablecomplexing agents include, but are not limited to, cyclodextrins,including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin,sulfobutylether-β-cyclodextrin, and sulfobutylether-7-β-cyclodextrin(CAPTISOL®, CyDex, Lenexa, Kans.).

The pharmaceutical compositions provided herein may be formulated forsingle or multiple dosage administration. The single dosage formulationscan be packaged in, e.g., an ampoule, a vial, or a syringe. In certainembodiments, the multiple dosage parenteral formulations contain anantimicrobial agent at bacteriostatic or fungistatic concentrations. Incertain embodiments, the parenteral formulations provided herein aresterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions are provided asready-to-use sterile solutions. In another embodiment, thepharmaceutical compositions are provided as sterile dry solubleproducts, including lyophilized powders and hypodermic tablets, to bereconstituted with a vehicle prior to use. In yet another embodiment,the pharmaceutical compositions are provided as ready-to-use sterilesuspensions. In yet another embodiment, the pharmaceutical compositionsare provided as sterile dry insoluble products to be reconstituted witha vehicle prior to use. In still another embodiment, the pharmaceuticalcompositions are provided as ready-to-use sterile emulsions.

The pharmaceutical compositions provided herein may be formulated asimmediate or modified release dosage forms, including delayed,sustained, pulsed, controlled, targeted, and programmed release forms.

The pharmaceutical compositions may be formulated as a suspension,solid, semisolid, or thixotropic liquid, for administration as animplanted depot. In one embodiment, the pharmaceutical compositionsprovided herein are dispersed in a solid inner matrix, which issurrounded by an outer polymeric membrane that is insoluble in bodyfluids but allows the active ingredient in the pharmaceuticalcompositions to diffuse through.

Suitable inner matrixes include polymethylmethacrylate,polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethylene terephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinyl acetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers, such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinyl alcohol, and cross-linked partiallyhydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include polyethylene, polypropylene,ethylene/vinyl acetate copolymers, ethylene/propylene copolymers,ethylene/ethyl acrylate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinyl chloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer.

Topical Administration

The pharmaceutical compositions provided herein may be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, includes (intra)dermal, conjunctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,urethral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein may be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, and dermal patches. Thetopical formulation of the pharmaceutical compositions provided hereinmay also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.Suitable pharmaceutically acceptable carriers and excipients are knownand described in the art. See, e.g., RC Rowe, Handbook of PharmaceuticalExcipients, 6^(th) ed., 2009, Pharmaceutical Press.

The pharmaceutical compositions may also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis, ormicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions provided herein may be provided in theform of ointments, creams, or gels. Suitable ointment vehicles includeoleaginous or hydrocarbon vehicles, including lard, benzoinated lard,olive oil, cottonseed oil, and other oils; white petrolatum;emulsifiable or absorption vehicles, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles,such as hydrophilic ointment; water-soluble ointment vehicles, includingpolyethylene glycols of varying molecular weight; and emulsion vehicles,either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,including cetyl alcohol, glyceryl monostearate, lanolin, and stearicacid. These vehicles are emollient but generally require addition ofantioxidants and preservatives.

Suitable cream bases can be oil-in-water or water-in-oil. Cream vehiclesmay be water-washable, and contain an oil phase, an emulsifier, and anaqueous phase. The oil phase is also called the “internal” phase, whichis generally comprised of petrolatum and a fatty alcohol such as cetylor stearyl alcohol. The aqueous phase usually, although not necessarily,exceeds the oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation may be a nonionic, anionic, cationic,or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughout aliquid carrier. Suitable gelling agents include crosslinked acrylic acidpolymers, such as carbomers, carboxypolyalkylenes, CARBOPOL®;hydrophilic polymers, such as polyethylene oxides,polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol;cellulosic polymers, such as HPC, HEC, HPMC, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums, such as tragacanthand xanthan gum; sodium alginate; and gelatin. To prepare a uniform gel,dispersing agents such as alcohol or glycerin can be added, or thegelling agent can be dispersed by trituration, mechanical mixing, and/orstirring.

The pharmaceutical compositions provided herein may be administeredrectally, urethrally, vaginally, or perivaginally in the form ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses, such as are described in Remington: The Science and Practiceof Pharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include bases or vehicles,such as stiffening agents, which produce a melting point in theproximity of body temperature. Suitable vehicles include, but are notlimited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax(polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax,and appropriate mixtures of mono-, di- and triglycerides of fatty acids,hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate,polyacrylic acid; and glycerinated gelatin. Combinations of the variousvehicles may be used. Rectal and vaginal suppositories may furthercomprise antioxidants as described herein, including bisulfite andsodium metabisulfite. Rectal and vaginal suppositories may be preparedby the compressed method or molding. The typical mass of a rectal andvaginal suppository is about 2 to about 3 g.

The pharmaceutical compositions provided herein may be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical compositions may be provided in the form of an aerosol orsolution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions mayalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; ornasal drops. For intranasal use, the powder may comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer may be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent, solvent or solventsystem for dispersing, solubilizing, or extending release of the activeingredient provided herein; and/or a propellant as solvent; and/or asurfactant, such as sorbitan trioleate, oleic acid, or an oligolacticacid.

The pharmaceutical compositions provided herein may be micronized to asize suitable for delivery by inhalation, such as about 50 micrometersor less, or about 10 micrometers or less. Particles of such sizes may beprepared using a comminuting method known to those skilled in the art,such as spiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters, and cartridges for use in an inhaler or insufflatormay be formulated to contain a powder mix of the pharmaceuticalcompositions provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form ofmonohydrates. Other suitable excipients or carriers include dextran,glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.The pharmaceutical compositions provided herein for inhaled/intranasaladministration may further comprise a suitable flavoring agent, such asmenthol and levomenthol, or sweeteners, such as saccharin or saccharinsodium.

The pharmaceutical compositions provided herein for topicaladministration may be formulated to be immediate release or modifiedrelease, including delayed, sustained, pulsed, controlled, targeted, andprogrammed release.

Co-Administration and Combinations

The terms “co-administration” and “in combination with” include theadministration of two or more pharmaceutically active agents (forexample, a compound of Formula I and another antiviral agent or secondagent) either simultaneously, concurrently, or sequentially with nospecific time limits. In one embodiment, both agents are present in thecell or in the patient's body at the same time or exert their biologicalor therapeutic effect at the same time. In one embodiment, the two ormore active agents are in the same composition or unit dosage form. Inanother embodiment, the two or more active agents are provided inseparate compositions or unit dosage forms.

The combinations above may conveniently be presented for use in the formof a pharmaceutical formulation and, thus, pharmaceutical formulationscomprising a combination as defined above together with apharmaceutically acceptable carrier thereof represent a further aspectof the invention.

The individual components of such combinations may be administeredeither sequentially or simultaneously, in separate or combinedpharmaceutical formulations. Appropriate doses of known active agentswill be readily appreciated by those skilled in the art.

The compounds of Formula I and other individual components of suchcombinations may be provided in therapeutic or subtherapeutic amounts.Irrespective of whether each component in the combination is itselfprovided in an amount that would otherwise be considered therapeutic orsubtherapeutic, and irrespective of whether the components are directedto the same or different specific therapeutic effects, a combinationaccording to the invention is administered in an amount that a skilledpractitioner would deem suitable for the treatment of HCV, as describedherein. In such cases, the combination is said to be administered in atherapeutic amount. Accordingly, an amount of a compound of theinvention might be considered subtherapeutic if administered alone, butwould be considered to be a therapeutic amount if the combination orco-administration regimen is considered therapeutically effective. Forexample, an amount of a compound of Formula I may be administered in anamount that achieves a therapeutic effect, e.g., a reduction inhepatitis C viral load, in combination with one or more other activeagents.

In some embodiments, a compound of Formula I may be administered incombination with one or more other antiviral agents. In someembodiments, a compound of Formula I may be administered in combinationwith two other antiviral agents. In some embodiments, a compound ofFormula I may be administered in combination with three other antiviralagents. In some embodiments, a compound of Formula I may be administeredin combination with four other antiviral agent. Such combinations aresometimes referred to as “cocktails.” Some combinations of antiviralagents are being used in the clinica to ameliorate the ability of HCV tomutate to overcome the inhibitory activity of a single agent. Use of acompound of Formula 1 in such combinations can therefore impart usefultherapeutic advantages.

Combinations or co-administration of the compounds of the invention withother active agents may desirably exhibit synergistic effects (i.e., theeffect that is achieved when active ingredients are administeredtogether is greater than the sum of the effects of each agentadministered separately) and/or a higher barrier to drug resistance. Forexample, if two agents are co-administered, their combined effect may besynergistic if a therapeutic effect is achieved notwithstanding that thetwo agents would not be expected to yield an equivalent therapeuticeffect if administered separately or together. On the contrary,antagonism of two agents may be said to exist if their combined effectis less than the sum of the effects of each agent administeredseparately. Synergy, drug resistance, and antagonism may be measuredusing any method that is generally accepted in the art, such as by wayof concentration response curves for a parameter of interest. Synergy,drug resistance, or antagonism for a given combination may be determinedfor inhibition of HCV infection, HCV polymerase activity, apharmacokinetic or pharmacodynamic effect, or the like.

Doses and dosing regimens of compounds of Formula I together with activesecond agents and combinations thereof should depend on the specificindication being treated, the age and condition of the patient, and theseverity of adverse effects, and may be adjusted accordingly by those ofskill in the art. Examples of doses and dosing regimens for other activemoieties can be found, for example, in Physician's Desk Reference, andwill require adaptation for use in the methods of the invention.

Accordingly, in some embodiments, there is administered to the patient atherapeutic amount of a combination comprising a compound of Formula Iand at least one other active agent to a patient in need thereof. Insome embodiments, the administered amount of at least one other activeagent is subtherapeutic. In some embodiments, the administered amount ofthe at least one other agent is therapeutic. In some embodiments, theadministered amount of the compound of Formula I is subtherapeutic. Inother embodiments, the administered amount of the compound of Formula Iis therapeutic.

The compounds of the invention may be administered as appropriate withone or more other active agents. Such active agents may be agents thathave activity against HCV directly or indirectly, e.g., compounds thatinhibit or reduce the replication or infectivity of HCV. Such and HCVagents include, among others, interferons, antiviral agents (e.g.,ribavirin, taribavirin (viramidine), amantadine), nucleoside HCV NS5Bpolymerase inhibitors, non-nucleoside HCV NS5B polymerase inhibitors,HCV protease inhibitors, HCV NS5A inhibitors, HCV NS4B inhibitors, HCVNS3 helicase inhibitors, host cell entry inhibitors, and humancyclophilin inhibitors.

In some embodiments, a compound of the invention may be administered incombination with one or more interferon molecules. Such interferonsinclude, without limitation, natural, recombinant, and modified (e.g.,PEG-linked, albumin-linked) interferon molecules. Interferons include,but are not limited to, interferon alfa-2a (Roferon®), interferonalpha-2b (Intron®), interferon alfacon-1 (Infergen®), peginterferonalfa-2a (Pegasys®) or peginterferon alfa-2b (PegIntron®), recombinantalfa interferon (BLX-883; Locteron®), and albinterferon alfa 2b(Zalbin®).

In some embodiments, a compound of Formula I may be administered incombination with an interferon and ribavirin. In such cases, thecompound of the invention may be said to be used to supplement thecurrent standard of care. In some other embodiments, a compound of theinvention is administered in combination with ribavirin.

In some embodiments, a compound of Formula I may be administered incombination with one or more compounds that inhibit the activity of theHCV serine protease (NS3-4A). Such protease inhibitors include, withoutlimitation, telaprevir (Incivek™; VX-950; Vertex), boceprevir(Victrelis™; SCH503034; Merck), TMC435 (Tibotec/Medevir), danoprevir(ITMN-191/R7227; InterMune/Roche), BI 201335 (Boehringer Ingelheim), BI12202 (Boehringer Ingelheim), vaniprevir (MK-7009; Merck), MK-5172(Merck), ABT-450 (Abbott/Enanta); VX500 (Vertex), PHX1766 (Phenomix),BILN2061 (Boehringer Ingelheim), GS-9256 (Gilead), GS-9451 (Gilead),BMS-650032 (Bristol-Myers Squibb), VX-985 (Vertex), ACH-1625(Achillion), ACH-2684 (Achillion), and narlaprevir (SCH900518; Merck).

In some embodiments, a compound of Formula I may be administered incombination with one or more nucleoside inhibitors of the HCV polymerase(NS5B). Suitable NI compounds include, among others, IDX184 (Idenix),RG7128 (R-7128, R05024048; Pharmasset/Roche), PSI-7851 (Pharmasset),PSI-938 (Pharmasset), PSI-7977 (Pharmasset), as well as phosphoramidatenucleotide analogs such as INX-189 (Inhibitex), TMC649128(Tibotec/Medevir). Combinations of compounds of the invention other NS5Binhibitors may be used, for example, combinations with ALS-2200 orALS-2158 (Vertex and Alios Biopharma)

In some embodiments, a compound of Formula I may be administered incombination with one or more non-nucleoside inhibitors of the HCVpolymerase (NS5B). Suitable NNI compounds include, without limitation,compounds that bind to or inhibit activity through one of the fouridentified NNI sites on the NS5B protein. See, Powdrill et al., Viruses,2010, 2:2169-95 and Appleby et al., “Viral RNA Polymerase Inhibitors,”Chapter 23 in Viral Genome Replication, Cameron et al., eds., SpringerScience+Business Media 2009. These compounds may be classified on thebasis of the site with which they interact.

In some embodiments, a compound of Formula I may be co-administered, orprovided in combination, with an NNI I inhibitor compound, an NNI IIinhibitor compound, an NNI III inhibitor compound or an NNI IV inhibitorcompound. Accordingly, in some embodiments, a compound of the inventionmay be administered in combination with one or more compounds selectedfrom among:

-   -   NNI I compounds including, among others, JTK-109 (Japan        Tobacco), BILB-1941 (Boehringer Ingelheim), MK-3281 (Merck), BI        207127 (Boehringer Ingelheim);    -   NNI II compounds including, among others, filibuvir (PF-868554;        Pfizer), VX-759 (VCH-759; Vertex), VCH-916 (Vertex), VX-222        (VCH-222; Vertex);    -   NNI III compounds including, among others, GSK625433 (Glaxo        SmithKline), ANA-598 (Anadys/Roche), ABT-333 (Abbott), ABT-072        (Abbott); or    -   NNI IV compounds including, among others, HCV-796        (ViroPharma/Wyeth), tegobuvir (GS-9190; Gilead), IDX375        (Idenix).

In other embodiments, a compound of Formula I may be administered incombination with one or more other NS5B polymerase inhibitors including,among others, BMS 791325 (Bristol-Myers Squibb), R1626 (Roche), A-848837(Abbott), and A-837093 (Abbott), as well as the compounds disclosed inInternational patent publications WO 02/100846 A1, WO 02/100851 A2, WO2004/052879 A2, WO 2004/052885 A1, WO 2006/072347 A2, WO 2006/119646 A1,WO 2008/017688 A1, WO 2008/043791 A2, WO 2008/058393 A1, WO 2008/059042A1, WO 2008/125599 A1, and WO 2009/000818 A1; U.S. Pat. Nos. 6,881,741B2, 6,887,877 B2, and 6,936,629 B2, 7,402,608 B2, and 7,569,600 B2; andYang et al., Bioorg Med Chem Lett, 2010, 20:4614-19.

In some embodiments, a compound of Formula I may be administered incombination with an active compound that inhibits another activity orfunction of HCV. For example, a compound of the invention may beadministered in combination with one or more compounds selected from:

-   -   NS5A (regulatory protein) inhibitors, e.g., BMS-790052        (Bristol-Myers Squibb), BMS-824383 (Bristol-Myers Squibb),        AZD7295 (AstraZeneca), PPI-461 (Presidio), PPI-688 (Presidio),        GS-5885 (Gilead), ACH-2928 (Achillion), IDX-719 (Idenix);    -   NS3 (peptidase/helicase) inhibitors, e.g., BMS-650032        (Bristol-Myers Squibb);    -   NS4B (regulatory protein) inhibitors, e.g., clemizole (Eiger        Biopharmaceuticals); Host-cell entry inhibitors, e.g., ITX5061        (iTherX); and    -   Cyclophilin inhibitors, such as cyclophilin-A inhibitors, e.g.,        Debio 025 (alisporivir), SCY-635, NIM811, and other cyclosporin        (ciclosporin) derivatives.

The compounds of Formula I may also be used in combination with othertherapeutic agents, for example, therapeutic vaccines, antifibroticagents, anti-inflammatory agents such as corticosteroids or NSAIDs,bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g.,theophylline), mucolytic agents, anti-muscarinics, anti-leukotrienes,inhibitors of cell adhesion (e.g., ICAM antagonists), anti-oxidants(e.g., N-acetylcysteine), cytokine agonists, cytokine antagonists, lungsurfactants and/or antimicrobial agents. The compounds of Formula I mayalso be used in combination with gene replacement therapy.

While the active moieties mentioned herein as second active agents maybe identified as free active moieties, salt forms (including salts withhydrogen or coordination bonds), solvates, or as non-covalentderivatives (e.g., chelates, complexes, and clathrates) of such activemoieties, it is to be understood that the given representativecommercial drug products are not limiting, and free active moieties, orsalts or other derivative forms of the active moieties may alternativelybe employed. Accordingly, reference to an active moiety should beunderstood to encompass not just the free active moiety but anypharmacologically acceptable salt, solvate, or other derivative formthat is consistent with the specified parameters of use.

EXAMPLES

The chemistry examples, synthetic schemata, and intermediates, providedherein are intended to illustrate synthetic routes suitable forpreparation of the compounds of the invention (and their intermediates),to assist in understanding the present invention. With appropriatemanipulation and protection of any chemical functionality, synthesis ofcompounds of Formula I is accomplished by methods analogous to thosedescribed herein. Suitable protecting groups can be found, for example,in P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in OrganicSynthesis, 4th Ed., 2006, Wiley Interscience.

Methods for testing for activity of the compounds of the invention aredescribed in the examples. The skilled persons will know of othermethods for identifying compounds having activity against the NS5Bpolymerase. For example, McKercher et al., Nucl Acids Res, 2004,32(2):422-31, describes a method for identifying NS5B inhibitorcompounds.

Synthetic intermediates were analyzed LC-MS. Final products wereanalyzed and confirmed by LC-MS and proton NMR. The LC-MS method: theinstrument was Agilent 1100 HPLC and Agilent 3200 mass spectrometer withESI(+) detector. The analytical column used was a Synergi Hydro-RPcolumn (00B-4375-E0; Phenomenex), and the compounds were eluted for 3minutes (10% to 95% acetonitrile in water, containing 0.1%trifluoroacetic acid).

Example 13-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

001 was prepared according to the following scheme:

To a stirred solution of 4-cyclohexanone (2 g, 17.8 mmol) andn-phenyltrifluoromethane-sulfonimide (7.6 g, 21.36 mmol) in THF (77 mL)under N₂ at −78° C. was added 1 M sodium bis-trimethylsilylamide in THF(20.0 mL, 19.6 mmol). The reaction was stirred 8 hours (hr), thenquenched with H₂O, and extracted with ether. The combined ether extractlayers were dried over MgSO₄, filtered and purified by silica gelchromatography to give 001B as a clear oil. MS calcd: (M+H)⁺: 245; MSfound: (M+H)⁺=245.

To a stirred solution of 001B (2.20 g, 9 mmol) in dioxane (38 mL) wasadded bis (pinacolato)diboron (2.74 g, 10.8 mmol), (Pd(dppf)Cl₂ (0.197g, 0.27 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.150 g, 0.27mmol), and AcOK (potassium acetate; 2.64 g, 27 mmol). The mixture wasdegassed by evacuating the reaction flask under vacuum followed by N₂back-fill (3×). Under N₂, the reaction was then heated to 90° C. andstirred overnight (approx. 16 hr). The reaction was cooled to roomtemperature (RT) and diluted with H₂O. The mixture was extracted withethyl acetate (EtOAc) (3×). The combined organic layers were washed withbrine, dried over MgSO₄, filtered, and then purified by silica gelchromatography to give compound 001C as a clear oil. MS calcd: (M+H)⁺:209. MS found: (M+H)⁺=209.

To a 50° C. solution of diiodomethane (9 g, 34 mmol) in CH₃CN (30 mL)were added sequentially tert-butyl nitrite (1.75 g, 17 mmol) followed bymethyl 3-amino-5-phenylthiophene-2-carboxylate (001D; 2.64 g, 11.3mmol). The reaction was stirred for 1.5 hr and then poured into asolution of sodium bisulfite (20 g in 50 mL H₂O) and stirred for 20minutes (min). The resulting mixture was extracted with EtOAc andconcentrated in vacuo. Silica gel column purification (0-5% EtOAc inhexane) gave 001E as yellow solid. MS calcd: (M+H)⁺=345. MS found:(M+H)⁺=345.

N,N′-dimethyl formamide (DMF) (10 mL) and H₂O (2 mL) were added to amixture of 3-bromopyridine-4-boronic acid (0.535 g, 2.65 mmol), compound001E (0.61 g, 1.77 mmol), Pd(dppf)Cl₂ (0.065 g, 0.089 mmol), and sodiumcarbonate (Na₂CO₃; 0.563 g, 5.31 mmol) under nitrogen (N₂) and stirredat 88° C. for 3 hr. The reaction was cooled to RT, and to it was addedice-water and EtOAc. The layers were separated and the aqueous layer wasback-extracted with EtOAc (2×). The combined organic layers were thenwashed with brine, dried over anhydrous Na₂SO₄, filtered over Celite®,and concentrated under reduced pressure. The product was purified byflash chromatography (silica gel) eluting with 0-5% methanol (MeOH) inCH₂Cl₂ to give 001F as an off-white solid. MS calcd: (M+H)⁺=375. MSfound: (M+H)⁺=375.

DMF (10 mL) and H₂O (2 mL) were added to a mixture of 001C (0.31 g, 1.4mmol), 001F (0.340 g, 0.91 mmol), Pd(dppf)Cl₂ (0.033 g, 0.0455 mmol),and Na₂CO₃ (0.3 g, 2.8 mmol) under N₂ and stirred at 88° C. for 3 hr.The reaction was cooled to RT, and to it was added ice-water and EtOAc.The layers were separated and the aqueous layer was back-extracted withEtOAc (2×). The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄, filtered over Celite®, and concentrated underreduced pressure. The residue was purified by flash chromatography(silica gel) eluting with 0-5% MeOH in CH₂Cl₂ to give compound 001G as asolid. MS calcd: (M+H)⁺=390. MS found: (M+H)⁺=390.

001G (100 mg, 0.257 mmol) was dissolved in MeOH (15 mL), and 10% Pd/C(20 mg) was added as the catalyst. Hydrogenation under 50 psi H₂ was runovernight. Filtration and concentration gave 001H. MS calcd: (M+H)⁺=392.MS found: (M+H)⁺=392.

Methyl iodide (0.08 mL, 1.278 mmol) was added to a solution of 001H (100mg, 0.256 mmol) in 5 mL of acetonitrile (ACN) and the mixture wasstirred for 3 hr at 80° C. The reaction mixture was cooled to RT andconcentrated in vacuo. The crude 001I was used directly in the nextstep. MS calcd: (M)⁺=406. MS found: (M)⁺=406.

Sodium borohydride (42 mg, 1.1 mmol) was added to a solution of 001I(111 mg, 0.275 mmol) in MeOH (6 mL) at RT with constant stirring. Thereaction mixture was stirred overnight at 80° C. The reaction mixturewas quenched with water (20 mL) and extracted with EtOAc (3×20 mL). Theorganic layers were combined, dried over anhydrous Na₂SO₄, andconcentrated to obtain the product as brown oil, which was purified bycolumn chromatography (silica gel, 0-10% MeOH in CH₂Cl₂) to yield the001J. MS calcd: (M+H)⁺=410. MS found: (M+H)⁺=410.

001J (50 mg) was dissolved in tetrahydrofuran (THF; 2 mL) and ethanol(EtOH; 1 mL). Lithium hydroxide solution (LiOH; 2 M, 0.5 mL) was thenadded. The reaction was stirred at RT for 16 hr, and then diluted withEtOAc. The organic layer was washed with water and concentrated. Thefinal product was precipitated out in hexane and washed more withhexane. The powder of compound 001 was obtained with lyophilization. MScalcd: (M+H)⁺=396. MS found: (M+H)⁺=396.

Example 25-Iodo-3-[1-methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

002 was prepared according to the following scheme:

To a 50° C. solution of diiodomethane (9 g, 34 mmol) in CH₃CN (30 mL)were added, sequentially, tert-butyl nitrite (1.75 g, 17 mmol) followedby methyl 3-amino-2-thiophenecarboxylate (1.77 g, 11.3 mmol). Thereaction was stirred for 1.5 hr and then poured into a solution ofsodium bisulfite (20 g in 50 mL H₂O) and stirred for 20 min. Theresulting mixture was extracted with EtOAc and concentrated in vacuo.Silica gel column separation (0-5% EtOAc in hexane) gave compound 002Aas light yellow solid. MS calcd: (M+H)⁺: 269. MS found: (M+H)⁺=269.

DMF (10 mL) and H₂O (2 mL) were added to a mixture of3-bromopyridine-4-boronic acid (0.535 g, 2.65 mmol), 002A (0.47 g, 1.77mmol), Pd(dppf)Cl₂ (0.065 g, 0.089 mmol), and Na₂CO₃ (0.563 g, 5.31mmol) under N₂ and the mixtures was stirred at 88° C. for 3 hr. Thereaction was cooled to RT, and to it was added ice-water and EtOAc. Theorganic layer was washed with water (3×) and the combined aqueous layerswere back-extracted with EtOAc (2×). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. The product was purified by flash chromatography(silica gel), eluting with 0-5% MeOH in CH₂Cl₂ to give 002B as anoff-white solid. MS calcd: (M+H)⁺: 299. MS found: (M+H)⁺=299.

DMF (10 mL) and H₂O (2 mL) were added to a mixture of4-methyl-cyclohexenyl-boronic ester (0.31 g, 1.4 mmol), 002B (0.27 g,0.91 mmol), Pd(dppf)Cl₂ (0.033 g, 0.0455 mmol), and Na₂CO₃ (0.3 g, 2.8mmol) under N₂, and the mixture was stirred at 92° C. for 4 hr. Thereaction was cooled to RT, and to it was added ice-water and EtOAc. Theorganic layer was washed with water (3×) and the combined aqueous layerswere back-extracted with EtOAc (2×). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. The product was purified by flash chromatography(silica gel), eluting with 0-5% MeOH in CH₂Cl₂ to give 002C as a solid.MS calcd: (M+H)⁺=314. MS found: (M+H)⁺=314.

102C (80.4 mg, 0.257 mmol) was dissolved in MeOH (15 mL), and 10% Pd/C(15 mg) was added as the catalyst. Hydrogenation under 50 psi H₂ was runovernight. Filtration and concentration gave compound 102D. MS calcd:(M+H)⁺=316. MS found: (M+H)⁺=316.

Methyl iodide (0.08 mL, 1.278 mmol) was added to a solution of (80.6 mg,0.256 mmol) of compound 102D in 5 mL of ACN, and the mixture was stirredfor 3 hr at 80° C. The reaction mixture was cooled to RT andconcentrated in vacuo. The crude 102E was used directly in the nextstep. MS calcd: (M)⁺=330. MS found: (M)⁺=330.

Sodium borohydride (42 mg, 1.1 mmol) was added to a solution of 002E(90.75 mg, 0.275 mmol) in MeOH (6 mL) at RT with constant stirring. Thereaction mixture was stirred overnight at 80° C. The reaction mixturewas quenched with water (20 mL) and extracted with EtOAc (3×20 mL). Theorganic layers were combined, dried over anhydrous Na₂SO₄, andconcentrated to obtain the compound as brown oil, which was purified bycolumn chromatography (silica gel, 0-10% MeOH in CH₂Cl₂) to yield 002F.MS calcd: (M+H)⁺=334. MS found: (M+H)⁺=334.

A solution of 002F (1 g, 3 mmol) in dry THF (10 mL) was added dropwiseat −77° C. under N₂ to 2 M lithium diisopropylamide (LDA) inTHF/heptane/ethylbenzene (3 mL) maintaining an internal temperature<−70° C. The stirring was continued at −77° C. for 2.5 hr. A solution ofiodine (2.3 g) in dry THF (5 mL) was added dropwise to the stirredreaction mixture maintaining an internal temperature <−70° C. Afterstirring under N₂ at −77° C. for 1.5 hr, the reaction mixture wasquenched by addition of saturated NH₄Cl solution and warmed to 0° C. Themixture was diluted with 5% sodium thiosulfate solution, then theorganic phase was separated and the aqueous phase was extracted withEtOAc. The combined organic phases were dried (Na₂SO₄), filtered, andevaporated. The product was dried to give 002G. MS calcd: (M+H)⁺=460. MSfound: (M+H)⁺=460.

002G (50 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated in hexane and washedmore with hexane. The powder of compound 002 was obtained afterlyophilization. MS calcd: (M+H)⁺=446. MS found: (M+H)⁺=446.

Example 35-(3,3-Dimethyl-but-1-ynyl)-3-[1-methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

To a 25 mL round bottom flask under N₂, 002G (1 eq.), copper iodide(0.15 eq.) and Pd(dppf)Cl₂ (0.05 eq.) were added. DMF, triethylamine(TEA; 4 eq.), and 3,3-dimethyl-but-1-yne (3 eq.) were added and thereaction mixture stirred at 60° C. for 2 hr under N₂. The reactionmixture was filtered over Celite® and washed with EtOAc. The solutionwas diluted with water and extracted (2×) with EtOAc. The organic phaseswere combined and washed (with water (2×). The organic layer wasseparated, dried (Na₂SO₄), evaporated, and purified by columnchromatography to give compound 003A. MS calcd: (M+H)⁺=414. MS found:(M+H)⁺=414.

003A (50 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated out in hexane andwashed more with hexane. The powder of 003 was obtained afterlyophilization. MS calcd: (M+H)⁺=400. MS found: (M+H)⁺=400.

Example 45-(4-Amino-phenyl)-3-[1-methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

DMF (10 mL) and H₂O (2 mL) were added to a mixture of[4-({[(1,1-dimethylethyl)oxy]-carbonyl}amino)phenyl]boronic acid (0.33g, 1.4 mmol), 002G (0.42 g, 0.91 mmol), Pd(dppf)Cl₂ (0.033 g, 0.0455mmol), and Na₂CO₃ (0.3 g, 2.8 mmol) under N₂, and the mixture wasstirred at 92° C. for 4 hr. The reaction was cooled to RT, and to it wasadded ice-water and EtOAc. The organic layer was washed with water (3×)and the combined aqueous layers were back-extracted with EtOAc (2×). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, and concentrated under reduced pressure. The product waspurified by flash chromatography (silica gel), eluting with 0-5% MeOH inCH₂Cl₂ to give 004A as an oil. MS calcd: (M+H)⁺=525. MS found:(M+H)⁺=525.

004A (0.19 g) was stirred in dichloromethane (DCM; 3 mL) andtrifluoroacetic acid (TFA; 1 mL) at RT under N₂ for 1 hr. The reactionwas evaporated in vacuo and the residue partitioned between sodiumbicarbonate solution and DCM. The organic phase was evaporated and driedin vacuo to give 004B. MS calcd: (M+H)⁺=425. MS found: (M+H)⁺=425.

004B (50 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated out in hexane andwashed more with hexane. The powder of 004 was obtained withlyophilization. MS calcd: (M+H)⁺=411. MS found: (M+H)⁺=411.

Example 53-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-(4-pyrazolo[1,5-a]pyrimidin-2-yl-phenyl)-thiophene-2-carboxylicacid

A solution of 3-(4-bromophenyl)-1H-pyrazol-5-amine (5.00 g) in aceticacid (80 mL) was treated with 1,1,3,3-tetramethoxypropane (4.13 g) andthe mixture heated at 110° C. for 1.5 hr. On cooling to RT, theprecipitated solid was isolated by filtration, washed with water (3×10mL) and dried in vacuo at 40° C. The residue was recrystallized fromacetic acid and dried in vacuo at 40° C. to give 005A. MS calcd: (M+H)⁺:274/276. MS found: (M+H)⁺=274/276.

A mixture of compound 005A (5 g), bis(pinacolato)diboron (6.7 g), AcOK(5.4 g) and Pd(dppf)Cl₂ (1 g) in dry 1,4-dioxane (20 mL) was heated to100° C. under N₂ for 15 hr. The solvent was evaporated and the residuepartitioned between water (10 mL) and DCM (30 mL). The aqueous phase wasextracted further with DCM (20 mL) and the combined organic layers wereevaporated. The residue was purified by SPE chromatography, eluting withcyclohexane/EtOAc (3:1) to give 005B. MS calcd: (M+H)⁺=322. MS found:(M+H)⁺=322.

DMF (10 mL) and H₂O (2 mL) were added to a mixture of[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazolo[1,5-a]pyrimidine(0.45 g, 1.4 mmol), 002 (0.4 g, 0.91 mmol), Pd(dppf)Cl₂ (0.033 g, 0.0455mmol), and Na₂CO₃ (0.3 g, 2.8 mmol) under N₂, and stirred at 92° C. for4 hr. The reaction was cooled to RT, and to it was added ice-water andEtOAc. The organic layer was washed with water (3×) and the combinedaqueous layers were back-extracted with EtOAc (2×). The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. The product was purified by flashchromatography (silica gel) to give 005. MS calcd: (M+H)⁺=513. MS found:(M+H)⁺=513.

Example 63-[1-Cyclopropylmethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

006 was prepared by the same method as 001, using cyclopropyl-methylbromide instead of methyl iodide. MS calcd: (M+H)⁺=436. MS found:(M+H)⁺=436.

Example 83-[1-(3-Hydroxy-propyl)-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

008 was prepared by the same method as 001, using tert-butyldimethylsilyl 3-iodopropyl ether instead of methyl iodide. MS calcd:(M+H)⁺=440. MS found: (M+H)⁺=440.

Example 93-[1-Isopropyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

009 was prepared by the same method as 001, using isopropyl iodideinstead of methyl iodide. MS calcd: (M+H)⁺=424. MS found: (M+H)⁺=424.

Example 115-(3-Hydroxy-3-methyl-but-1-ynyl)-3-[1-methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

011 was prepared by the same method as 003, using 2-methyl-3-butyn-2-olinstead of 3,3-dimethyl-but-1-yne. MS calcd: (M+H)⁺=402. MS found:(M+H)⁺=402.

Example 125-(4-tert-Butoxycarbonylamino-phenyl)-3-[1-methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

004A (50 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated out in hexane andwashed more with hexane. The powder of 012 was obtained withlyophilization. MS calcd: (M+H)⁺=511. MS found: (M+H)⁺=511.

Example 133-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid

1,3-Thiazole-4-carboxylic acid (100 mg) was dissolved in DMF (3 mL).2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU; 325 mg) and diisopropylethylamine (DIPEA;0.35 mL) were added and the reaction mixture was stirred at RT for 15min. Compound 004B (161 mg, 0.38 mmol) was added and the reactionmixture was stirred at RT for 1 hr. The reaction mixture was evaporatedin vacuo and the residue was dissolved in DCM. This was washed withNaHCO₃ solution (2×) followed by 2 N HCl (2×). The DCM was separated andconcentrated to obtain the compound as a brown oil, which was purifiedby column chromatography to give 013A. MS calcd: (M+H)⁺=536. MS found:(M+H)⁺=536.

013A (50 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated out in hexane andwashed more with hexane. The powder of 013 was obtained withlyophilization. MS calcd: (M+H)⁺=521. MS found: (M+H)⁺=521.

Example 145-(3,3-Dimethyl-but-1-ynyl)-3-[1-ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

014 was prepared according to the following scheme.

Ethyl iodide (0.08 mL, 1.278 mmol) was added to a solution of (80.6 mg,0.256 mmol) of 002D in 5 mL of ACN and the mixture was stirred for 3 hrat 80° C. The reaction mixture was cooled to RT and concentrated invacuo. The crude 014A was used directly in the next step. MS calcd: forM⁺=345. MS found: M⁺=345.

Sodium borohydride (42 mg, 1.1 mmol) was added to a solution of 014A(90.75 mg, 0.275 mmol) in MeOH (6 mL) at RT with constant stirring. Thereaction mixture was stirred overnight at 80° C. The reaction mixturewas quenched with water (20 mL) and extracted with EtOAc (3×20 mL). Theorganic layers were combined, dried over anhydrous Na₂SO₄, andconcentrated to obtain the compound as brown oil, which was purified bycolumn chromatography (silica gel, 0-10% MeOH in CH₂Cl₂) to yield 014B.MS calcd: (M+H)⁺=348. MS found: (M+H)⁺=348.

A solution of 014B (1 g, 3 mmol) in dry THF (10 mL) was added dropwiseat −77° C. under N₂ to 2 M LDA in THF/heptane/ethylbenzene (3 mL), whilemaintaining an internal temperature <−70° C. The stirring continued at−77° C. for 2.5 hr. A solution of iodine (2.3 g) in dry THF (5 mL) wasadded dropwise to the stirred reaction mixture while maintaining aninternal temperature <−70° C. After stirring under N₂ at −77° C. for 1.5hr, the reaction mixture was quenched by addition of saturated NH₄Clsolution and warmed to 0° C. The mixture was diluted with 5% sodiumthiosulfate solution, then the organic phase was separated and theaqueous phase was extracted with EtOAc. The combined organic phases weredried (Na₂SO₄), filtered and evaporated. The product was dried to give014C. MS calcd: (M+H)⁺=474. MS found: (M+H)⁺=474.

To a 25 mL round bottom flask under N₂, 014C (1 eq.), copper iodide(0.15 eq.) and Pd(dppf)Cl₂ (0.05 eq.) are added. DMF, TEA (4 eq.), and3,3-dimethyl-but-1-yne (3 eq.) were added and the reaction mixture wasstirred at 60° C. for 2 hr under a N₂ atmosphere. The reaction mixturewas filtered on Celite® and washed with EtOAc. The filtrate was dilutedwith water, and extracted twice with EtOAc. The organic phases werecombined and washed twice with water. The organic layer was separated,dried (Na₂SO₄), evaporated, and purified by column chromatography togive 014D. MS calcd: (M+H)⁺=428. MS found: (M+H)⁺=428.

Compound 014D (50 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH(2 M, 0.5 mL) was then added. The reaction was stirred at RT for 16 hr,and then diluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated out in hexane andwashed more with hexane. The powder of 014 was obtained withlyophilization. MS calcd: (M+H)⁺=414. MS found: (M+H)⁺=414.

Example 153-[1-Ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-(4-pyrazolo[1,5-a]pyrimidin-2-yl-phenyl)-thiophene-2-carboxylicacid

014C (50 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated out in hexane andwashed more with hexane. The powder of 014E was obtained withlyophilization. MS calcd: (M+H)⁺=460. MS found: (M+H)⁺=460.

015 was then prepared by the same method as 005, using intermediate 014Einstead of 002. MS calcd: (M+H)⁺=526. MS found: (M+H)⁺=526.

Example 165-Cyclohexylethynyl-3-[1-ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

016 was prepared by the same method as 014, using cyclohexylacetyleneinstead 3,3-dimethyl-but-1-yne. MS calcd: (M+H)⁺=440. MS found:(M+H)⁺=440.

Example 185-(4-Acetylamino-phenyl)-3-[1-ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

DMF (10 mL) and H₂O (2 mL) were added to a mixture of[4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)phenyl]boronic acid (0.33 g,1.4 mmol), 014C (0.43 g, 0.91 mmol), Pd(dppf)Cl₂ (0.033 g, 0.0455 mmol)and Na₂CO₃ (0.3 g, 2.8 mmol) under N₂, and stirred at 92° C. for 4 hr.The reaction was cooled to RT, and to it was added ice-water and EtOAc.The organic layer was washed with water (3×) and the combined aqueouslayers were back-extracted with EtOAc (2×). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄, and concentratedunder reduced pressure. The product was purified by flash chromatography(silica gel), eluting with 0-5% MeOH in CH₂Cl₂ to give 018A. MS calcd:(M+H)⁺=539. MS found: (M+H)⁺=539.

018A (0.19 g) was stirred in DCM (3 mL) and TFA (1 mL) at RT under N₂for 1 hr. The reaction was evaporated in vacuo and the residuepartitioned between NaHCO₃ solution and DCM. The organic phase wasevaporated and dried in vacuo to give 018B. MS calcd: for(C₂₄H₃₄N₂O₃S+H)⁺=439. MS found: (M+H)⁺=439.

Acetyl chloride (9.6 mg, 0.12 mmol) was added at 0-15° C. to a solutionof TEA (40 mg, 0.3 mmol) and 018B (23.4 mg. 0.053 mmol) in DCM (3 mL).After 20 min the mixture was warmed rapidly to RT. After being stirred30 min, DCM (5 mL) and 2N NaOH (1 mL) was added, and the organic layerwas separated and washed with water. The organic layers were separated,dried and concentrated to give a brown oil. Purification by silica gelcolumn chromatography gave 018C. MS calcd: (M+H)⁺=481. MS found:(M+H)⁺=481.

018C (20 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated out in hexane andwashed more with hexane. The powder of 018 was obtained withlyophilization. MS calcd: (M+H)⁺=467. MS found: (M+H)⁺=467.

Example 193-[1-Ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid

019 was prepared by the same method as 013, using 018B instead of 004B.MS calcd: (M+H)⁺=535. MS found: (M+H)⁺=535.

Example 205-(4-Benzoylamino-phenyl)-3-[1-ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

020 was prepared by the same method as 018, using benzoyl chlorideinstead of acetyl chloride. MS calcd: (M+H)⁺=529. MS found: (M+H)⁺=529.

Example 215-(3-Amino-3-methyl-but-1-ynyl)-3-[1-ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

To a 25 mL round bottom flask under N₂, 014C (1 eq.), copper iodide(0.15 eq.) and Pd(dppf)Cl₂ (0.05 eq.) were added. DMF, TEA (4 eq.), and1,1-dimethylpropargylamine (3 eq.) were added, and the reaction mixturewas stirred at 60° C. for 2 hr under a N₂ atmosphere. The reactionmixture was filtered over Celite® and washed with EtOAc. The filtratewas diluted with water and extracted twice with EtOAc. The organic phasewere combined and washed twice with water. The organic layer wasseparated, dried (Na₂SO₄), evaporated, and purified by columnchromatography to give intermediate 021A. MS calcd: (M+H)⁺=429. MSfound: (M+H)⁺=429.

021A (25 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated out in hexane andwashed more with hexane. The powder of 021 was obtained withlyophilization. MS calcd: (M+H)⁺=415. MS found: (M+H)⁺=415.

Example 223-[1-Ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{3-methyl-3-[(thiazole-4-carbonyl)-amino]-but-1-ynyl}-thiophene-2-carboxylicacid

022 was prepared by the same method as 013, using 021A instead of 004B.MS calcd: (M+H)⁺=526. MS found: (M+H)⁺=526.

Example 235-(3-Dimethylamino-3-methyl-but-1-ynyl)-3-[1-ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

021A (40 mg, 0.093 mmol), formaldehyde (14 mg, 0.45 mmol), and sodiumtriacetoxyborohydride (0.21 g, 1 mmol) were mixed in 1,2-dichloroethane(DCE; 5 mL). The reaction was stirred at RT overnight. The reaction wasquenched with saturated aqueous NaHCO₃, and the product was extractedwith EtOAc (20 mL). The EtOAc extract was dried (MgSO₄), and the solventwas evaporated. Separation by chromatography gave 023A as a yellowsemisolid. MS calcd: (M+H)⁺=457. MS found: (M+H)⁺=457.

023A (25 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated out in hexane andwashed more with hexane. The powder of 023 was obtained withlyophilization. MS calcd: (M+H)⁺=443. MS found: (M+H)⁺=443.

Example 245-(3-Acetylamino-phenyl)-3-[1-ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

DMF (10 mL) and H₂O (2 mL) were added to a mixture of[3-({[(1,1-dimethylethyl)oxy]-carbonyl}amino)phenyl]boronic acid (0.33g, 1.4 mmol), 014C (0.43 g, 0.91 mmol), Pd(dppf)Cl₂ (0.033 g, 0.0455mmol), and Na₂CO₃ (0.3 g, 2.8 mmol) under N₂, and stirred at 92° C. for4 hr. The reaction was cooled to RT, and to it was added ice-water andEtOAc. The organic layer was washed with water (3×) and the combinedaqueous layers were back-extracted with EtOAc (2×). The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. The product was purified by flashchromatography (silica gel), eluting with 0-5% MeOH in CH₂Cl₂ to give024A. MS calcd: (M+H)⁺=539. MS found: (M+H)⁺=539.

024A (0.19 g) was stirred in DCM (3 mL) and TFA (1 mL) at RT under N₂for 1 hr. The reaction was evaporated in vacuo and the residuepartitioned between saturated sodium bicarbonate solution and DCM. Theorganic phase was evaporated and dried in vacuo to give 024B. MS calcd:(M+H)⁺=439. MS found: (M+H)⁺=439.

Acetyl chloride (9.6 mg, 0.12 mmol) was added at 0-15° C. to a solutionof TEA (40 mg, 0.3 mmol) and 024B (23.4 mg. 0.053 mmol) in DCM (3 mL).After 20 min the mixture was warmed rapidly to RT. After being stirred30 min, DCM (5 mL) and 2 N NaOH (1 mL) was added, and the organic layerwas separated and washed with water. The organic layers were separated,dried and concentrated, giving a brown oil. Separation by columnchromatography gave 024C. MS calcd: (M+H)⁺=481. MS found: (M+H)⁺=481.

024C (24 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated out in hexane andwashed more with hexane. The powder of 024 was obtained withlyophilization. MS calcd: (M+H)⁺=467. MS found: (M+H)⁺=467.

Example 253-[1-Ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{3-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid

025 was prepared by the same method as 019, using 024B instead of 018B.MS calcd: (M+H)⁺=536. MS found: (M+H)⁺=536.

Example 265-(3-Amino-phenyl)-3-[1-ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

024B (24 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated out in hexane andwashed more with hexane. The powder of 026 was obtained withlyophilization. MS calcd: (M+H)⁺=425. MS found: (M+H)⁺=425.

Example 303-[1-Ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-(3-methyl-hex-1-ynyl)-thiophene-2-carboxylicacid

030 was prepared by the same method as 014, using 3-methyl-1-hexyneinstead of 3,3-dimethyl-but-1-yne. MS calcd: (M+H)⁺=428. MS found:(M+H)⁺=428.

Example 315-Cyclopentylethynyl-3-[1-ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

031 was prepared by the same method as 014, using cyclopentylacetyleneinstead of 3,3-dimethyl-but-1-yne. MS calcd: (M+H)⁺=426. MS found:(M+H)⁺=426.

Example 335-(3,3-Diethoxy-prop-1-ynyl)-3-[1-ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

033 was prepared by the same method as 014, using propargylaldehydediethyl acetal instead of 3,3-dimethyl-but-1-yne. MS calcd: (M+H)⁺=460.MS found: (M+H)⁺=460.

Example 355-(4-Carboxy-phenyl)-3-[1-ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

DMF (10 mL) and water (2 mL) were added to a mixture of4-carboxyphenylboronic acid (0.23 g, 1.4 mmol), 014C (0.43 g, 0.91mmol), Pd(dppf)Cl₂ (0.033 g, 0.0455 mmol), and Na₂CO₃ (0.3 g, 2.8 mmol)under N₂, and stirred at 92° C. for 4 hr. The reaction was cooled to RT,and to it was added ice-water and EtOAc. The organic layer was washedwith water (3×) and the combined aqueous layers were back-extracted withEtOAc (2×). The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄, and concentrated under reduced pressure. Theproduct was purified by flash chromatography (silica gel), eluting with0-5% MeOH in CH₂Cl₂ to give 035A. MS calcd: (M+H)⁺=468. MS found:(M+H)⁺=468.

035A (25 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated out in hexane andwashed more with hexane. The powder of 035 was obtained withlyophilization. MS calcd: (M+H)⁺=454. MS found: (M+H)⁺=454.

Example 363-[5-(4-Methyl-cyclohexyl)-1-(toluene-4-sulfonyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

To a solution of 004B (25 mg, 0.058 mmol) and TEA (0.022 mL, 0.174 mmol)in CH₂Cl₂ (6 mL) cooled by an ice-water bath was added p-toluenesulfonylchloride (22 mg, 0.115 mmol). The reaction was allowed to warm to RTovernight. The reaction mixture was concentrated and purified bypreparative thin layer chromatography (prep-TLC, 50% EtOAc in hexane) toyield 036A (21 mg, 66%).

036A (21 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH solution(2 M, 0.5 mL) was then added. The reaction was stirred at RT for 16 hr.The reaction mixture was acidified with 1 M HCl to pH 4-5 andconcentrated to remove the organic solvent, then extracted with EtOAc(3×10 mL). The combined organic layers were washed with 10% citric acidaq, water, brine, then dried over MgSO₄ and concentrated. The residuewas then purified by prep-TLC to give 036. MS calcd: (M+H)⁺=536. MSfound: (M+H)⁺=536.

Example 374-(2-Carboxy-5-phenyl-thiophen-3-yl)-5-(4-methyl-cyclohexyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

037 was prepared by the same method as 036, using di-tert-butyldicarbonate instead of p-toluenesulfonyl chloride. MS calcd: (M+H)⁺=482.MS found: (M+H)⁺=482.

Example 393-[1-Methanesulfonyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

039 was prepared by the same method as 036, using methanesulfonylchloride instead of p-toluenesulfonyl chloride. MS calcd: (M+H)⁺=460. MSfound: (M+H)⁺=460.

Example 403-[5-(4-Methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

040A was prepared by the same method as 001j, using benzyl bromideinstead of methyl iodide. MS calcd: (M+H)⁺=486. MS found: (M+H)⁺=486.

A solution of the product from 040A (81 mg, 0.17 mmol) in1,2-dichoroethane (5 mL) was treated with 1-choroethylchoroformate (49μL, 0.51 mmol) and the mixture heated to reflux for 4 hr. Methanol (2mL) was carefully added to the mixture and heating continued for 2 hr.The mixture was allowed to cool to RT and concentrated to give 040B asan oil (66 mg, 99%). The crude 040B was used without furtherpurification.

040B (20 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr. Thereaction mixture was acidified with 1 M HCl to pH 4-5 and concentratedto remove organic solvent then extracted with EtOAc (3×10 mL). Thecombined organic layers was washed with brine, dried over MgSO₄, andconcentrated to obtain the crude product, which was then purified byprep-TLC to give 040. MS calcd: (M+H)⁺=382. MS found: (M+H)⁺=382.

Example 40X Methyl3-(5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-phenylthiophene-2-carboxylate

001H (240 mg, 0.61 mmol) was dissolved in ACN (5 mL) and treated withbenzyl bromide (0.11 mL, 0.90 mmol). The resultant reaction mixture wasstirred for 3 hr at 80° C., cooled to RT, and concentrated in vacuo. Thecrude reaction product was carried to the next step withoutpurification. The intermediate was dissolved in MeOH (10 mL) and treatedwith sodium borohydride (0.80 g, 2.2 mmol) under constant stirring. Thereaction mixture was stirred overnight at 80° C., quenched with water(20 mL), and extracted with EtOAc (3×20 mL). The combined organic layerwas dried under anhydrous Na₂SO₄ and concentrated to obtain the compoundas a brown oil. Purification by flash chromatography (silica gel, 0-5%MeOH in methylene chloride) afforded the intermediate compound (210 mg,yield 77%). The intermediate compound (210 mg, 0.432 mmol) was dissolvedin DCE (5 mL) and treated with 1-chloroethylchloroformate (70 μL, 0.60mmol). The resultant mixture was stirred under reflux for 4 hr. MeOH (2mL) was added to the reaction mixture in small portions and the heatingwas continued for an additional 2 hr. The mixture was allowed to cool toRT and concentrated to afford crude 040X (180 mg) as an oil, which wasused in additional chemistry without purification. MS calcd: (M+H)⁺=396.MS found: (M+H)⁺=396.

Example 413-[1-Methyl-4-(4-methyl-cyclohexyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-5-phenyl-thiophene-2-carboxylicacid

To a stirred solution of 001E (2.41 g, 9 mmol) in dioxane (38 mL) wasadded his (pinacolato)diboron (2.74 g, 10.8 mmol), Pd(dppf)Cl₂ (0.197 g,0.27 mmol), dppf (0.150 g, 0.27 mmol), and AcOK (2.64 g, 27 mmol). Themixture was degassed by evacuating the reaction flask under vacuumfollowed by N₂ back-fill (3×). Under N₂, the reaction was then heated to90° C. and stirred overnight (approx. 16 hr). The reaction was cooled toRT and diluted with H₂O. The mixture was extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and then purified by silica gel chromatography to give 041A asa solid. MS calcd: (M+H)⁺: 263. MS found: (M+H)⁺=263.

DMF (5 mL) and H₂O (1 mL) were added to a mixture of3-bromopyridine-4-boronic acid (0.27 g, 1.3 mmol), 001B (0.31 g, 1.3mmol), Pd(dppf)Cl₂ (0.048 g, 0.065 mmol) and Na₂CO₃ (0.41 g, 3.9 mmol)under N₂ and stirred at 90° C. for 4 hr. The reaction was cooled to RT,and to it was added ice-water and EtOAc. The layers were separated andthe organic layer was washed with water (3×) and the combined aqueouslayers were back-extracted with EtOAc (2×). The combined organic layerswere then washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. The product was purified by flashchromatography (silica gel) eluting with 0-5% MeOH in CH₂Cl₂ to give041B as an off-white solid. MS calcd: (M+H)⁺: 253. MS found: (M+H)⁺=253.

DMF (5 mL) and H₂O (1 mL) were added to a mixture of 041A (0.26 g, 1.0mmol), compound 041B (0.28 g, 1.1 mmol), Pd(dppf)Cl₂ (0.037 g, 0.05mmol) and Na₂CO₃ (0.41 g, 3.9 mmol) under N₂, and stirred at 90° C. for4 hr. The reaction was cooled to RT, and to it was added ice-water andEtOAc. The layers were separated and the organic layer was washed withwater (3×) and the combined aqueous layers were back-extracted withEtOAc (2×). The combined organic layers were then washed with brine,dried over anhydrous Na₂SO₄, and concentrated under reduced pressure.The product was purified by flash chromatography (silica gel) elutingwith 0-5% MeOH in CH₂Cl₂ to give compound 041C as an off-white solid. MScalcd: (M+H)⁺: 290. MS found: (M+H)⁺=390.

041C (100 mg, 0.257 mmol) was dissolved in MeOH (15 mL), and 10% Pd/C(20 mg) was added as the catalyst. Hydrogenation under 50 psi H₂ was runovernight. Filtration and concentration gave 041D. MS calcd: (M+H)⁺=392.MS found: (M+H)⁺=392.

Methyl iodide (0.08 mL, 1.278 mmol) was added to a solution of 041D (99mg, 0.25 mmol) in ACN (5 mL), and the mixture was stirred for 3 hr at80° C. The reaction mixture was cooled to RT and concentrated in vacuo.The crude 041E was used directly in the next step. MS calcd: (M)⁺=406.MS found: (M)⁺=406.

Sodium borohydride (42 mg, 1.1 mmol) was added to a solution of 041E(110 mg, 0.27 mmol) in MeOH (6 mL) at RT with constant stirring. Thereaction mixture was stirred overnight at 80° C. The reaction mixturewas quenched with water (20 mL) and extracted with EtOAc (3×20 mL). Theorganic layers were combined, dried over anhydrous Na₂SO₄, andconcentrated to obtain the product as brown oil, which was purified bycolumn chromatography (silica gel, 0-10% MeOH in CH₂Cl₂) to yield 041F.MS calcd: (M+H)⁺=410. MS found: (M+H)⁺=410.

041F (50 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated out in hexane andwashed more with hexane. The powder of 041 was obtained withlyophilization. MS calcd: (M+H)⁺=396. MS found: (M+H)⁺=396.

Example 423-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(pyridine-2-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid

042 was prepared by the same method as 013, using 2-pyridinecarboxylicacid instead of 1,3-thiazole-4-carboxylic acid. MS calcd: (M+H)⁺=516. MSfound: (M+H)⁺=516.

Example 433-[1-Benzyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

043 was prepared by the same method as 001, using benzyl bromide insteadof methyl iodide. MS calcd: (M+H)⁺=472. MS found: (M+H)⁺=472.

Example 453-[5-(4-Methyl-cyclohexyl)-1-(pyrazine-2-carbonyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

045 was prepared by the same method as 071, using pyrazine-2-carbonylchloride instead of acetyl chloride. MS calcd: (M+H)⁺=489. MS found:(M+H)⁺=489.

Example 465-(3,3-Dimethyl-but-1-ynyl)-3-[1-methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

046 was prepared by the same method as 003. The pure trans-1-methylisomer was isolated by preparative thin layer chromatography viarepeated migration with 3% MeOH in dichloromethane. MS calcd:(M+H)⁺=400. MS found: (M+H)⁺=400.

Example 473-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid

047 was prepared by the same method as 013. The pure trans-1-methylisomer was isolated by preparative thin layer chromatography viarepeated migration with 3% MeOH in dichloromethane. MS calcd:(M+H)⁺=522. MS found: (M+H)⁺=522.

Example 483-[1-Ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(2-methyl-thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid

048 was prepared by the same method as compound 019, using2-methyl-1,3-thiazole-4-carboxylic acid instead of1,3-thiazole-4-carboxylic acid. MS calcd: (M+H)⁺=550. MS found:(M+H)⁺=550.

Example 503-[1-Ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(thiazole-5-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid

050 was prepared by the same method as 019, using1,3-thiazole-5-carboxylic acid instead of 1,3-thiazole-4-carboxylicacid. MS calcd: (M+H)⁺=536. MS found: (M+H)⁺=536.

Example 515-{4-[(1,5-Dimethyl-1H-pyrazole-3-carbonyl)-amino]-phenyl}-3-[1-ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

051 was prepared by the same method as 019, using1,5-dimethyl-1H-pyrazole-3-carboxylic acid instead of1,3-thiazole-4-carboxylic acid. MS calcd: (M+H)⁺=547. MS found:(M+H)⁺=547.

Example 533-[1-Ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(5-methyl-isoxazole-3-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid

053 was prepared by the same method as 019, using5-methylisoxazole-3-carboxylic acid instead of 1,3-thiazole-4-carboxylicacid. MS calcd: (M+H)⁺=534. MS found: (M+H)⁺=534.

Example 595-{3-Fluoro-4-[(thiazole-4-carbonyl)-amino]-phenyl}-3-[1-methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

DMF (10 mL) and H₂O (2 mL) were added to a mixture of4-amino-3-fluorophenylboronic acid (0.26 g, 1.4 mmol), 002G (0.42 g,0.91 mmol), Pd(dppf)Cl₂ (0.033 g, 0.0455 mmol), and Na₂CO₃ (0.3 g, 2.8mmol) under N₂. The mixture was stirred at 92° C. for 4 hr. The reactionwas cooled to RT, and to it was added ice-water (5 mL) and EtOAc (50mL). The organic layer was washed with water (2×10 mL) and the combinedaqueous layers were back-extracted with EtOAc (10 mL). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. The product was purified by flashchromatography (silica gel), eluting with 0-5% MeOH in CH₂Cl₂ to give059A as an oil. MS calcd: (M+H)⁺=443. MS found: (M+H)⁺=443.

1,3-Thiazole-4-carboxylic acid (100 mg) was dissolved in DMF (3 mL). Toit were added HATU (325 mg) and DIPEA (0.35 mL) and the reaction mixturewas stirred at RT for 15 min. Compound 059A (168 mg, 0.38 mmol) wasadded and the reaction mixture was stirred at RT for 4 hr. The reactionmixture was evaporated in vacuo and the residue was dissolved in DCM (50mL). This was washed with sodium bicarbonate solution (2×10 mL) followedby brine. The organic layer was concentrated and purified by columnchromatography with 0-5% MeOH in DCM as eluent to give pure 059B. MScalcd: (M+H)⁺=554. MS found: (M+H)⁺=554.

059B (50 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated out in hexane andwashed once with hexane. The powder of 059 was obtained withlyophilization. MS calcd: (M+H)⁺=540. MS found: (M+H)⁺=540.

Example 605-{2-Fluoro-4-[(thiazole-4-carbonyl)-amino]-phenyl}-3-[1-methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

060 was prepared by the same method as 059, using4-amino-2-fluorophenylboronic acid pinacol ester instead of4-amino-3-fluorophenylboronic acid. MS calcd: (M+H)⁺=540. MS found:(M+H)⁺=540.

Example 623-[1-Ethyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-[4-(pyridin-2-ylcarbamoyl)-phenyl]-thiophene-2-carboxylicacid

062 was prepared according to the following scheme:

To solid 4-iodobenzoic acid (5 mmol) was slowly added thionyl chloride(10 mL). The reaction was refluxed for 4 hr, and the reaction mixturewas then concentrated to dryness to give compound 062A.

Crude 062A was dissolved in 1,2-dichloroethane (20 mL), and to it wasadded 2-aminopyiridine (5 mmol), TEA (2 mL), and DMAP (10 mg). Themixture was reluxed for 24 hr, and then concentrated. The crude productwas then purified by column chromatography, using 0-100% EtOAc in DCM togive 062B.

Compound 062C was prepared by the same method as 005B, using 062Binstead of 005A.

062 was prepared by the same method as 005, using intermediates 062C and014E instead of 005B and 002. MS calcd: (M+H)⁺=530. MS found:(M+H)⁺=530.

Example 633-[5-(2-Cyclopentyl-ethyl)-1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

To a 25 mL round bottom flask were added 001F (187 mg, 0.5 mmol), copperiodide (0.15 eq.) and Pd(dppf)Cl₂ (0.05 eq.), DMF (5 mL), TEA (4 eq.),and cyclopentylacetylene (3 eq.). The reaction mixture was stirred at60° C. for 2 hr under a N₂ atmosphere. The reaction mixture was filteredthrough Celite® and washed with EtOAc. The filtrate was diluted withwater, and extracted twice with EtOAc. The organic phases were combinedand washed twice with water. The organic layer was separated, dried(Na₂SO₄), evaporated, and purified by column chromatography to give063A. MS calcd: (M+H)⁺=388. MS found: (M+H)⁺=388.

Compound 063A (100 mg, 0.257 mmol) was dissolved in MeOH (15 mL), and10% Pd/C (20 mg) was added as the catalyst. Hydrogenation under 50 psiH₂ was run overnight. Filtration and concentration gave 063B. MS calcd:(M+H)⁺=392. MS found: (M+H)⁺=392.

Methyl iodide (0.08 mL, 1.278 mmol) was added to a solution of 063B (100mg, 0.256 mmol) in 5 mL of ACN and the mixture was stirred for 3 hr at80° C. The reaction mixture was cooled to RT and concentrated in vacuo.The crude 063C was used in the next step. MS calcd: (M)⁺=406. MS found:(M)⁺=406.

Sodium borohydride (42 mg, 1.1 mmol) was added to a solution of 063C(111 mg, 0.275 mmol) in MeOH (6 mL) at RT with constant stirring. Thereaction mixture was stirred overnight at 80° C. The reaction mixturewas quenched with water (20 mL) and extracted with EtOAc (3×20 mL). Theorganic layers were combined, dried over anhydrous Na₂SO₄, andconcentrated to obtain the product as brown oil, which was purified bycolumn chromatography (silica gel, 0-10% MeOH in CH₂Cl₂) to yield the063D. MS calcd: (M+H)⁺=410. MS found: (M+H)⁺=410.

063D (50 mg) was dissolved in tetrahydrofuran (THF; 2 mL) and EtOH (1mL). LiOH (2 M, 0.5 mL) was then added. The reaction was stirred at RTfor 16 hr, and then diluted with EtOAc. The organic layer was washedwith water and concentrated. The final product was precipitated out inhexane and washed once more with hexane. The powder of 063 was obtainedwith lyophilization. MS calcd: (M+H)⁺=396. MS found: (M+H)⁺=396.

Example 643-[1-Methyl-5-(4-trifluoromethyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

064 was prepared by the same method as 001, using4-(trifluoromethyl)cyclohexan-1-one instead of 4-methylcyclohexanone. MScalcd: (M+H)⁺=450. MS found: (M+H)⁺=450.

Example 655-(3,3-Dimethyl-but-1-ynyl)-3-[4-(4-methyl-cyclohexyl)-1-(tetrahydro-pyran-4-ylmethyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-thiophene-2-carboxylicacid

065 was prepared by the same method as 117 (see below), using4-formyltetrahydropyran instead of tetrahydrofuran-3-carboxaldehyde. MScalcd: (M+H)⁺=484. MS found: (M+H)⁺=484.

Example 673-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[methyl-(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid

067 was prepared by the same method as 059, using4-(aminomethyl)benzeneboronic acid instead of4-amino-3-fluorophenylboronic acid. MS calcd: (M+H)⁺=536. MS found:(M+H)⁺=536.

Example 685-(3,3-Dimethyl-but-1-ynyl)-3-[1-methyl-5-(4-methyl-cyclohex-1-enyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

Methyl iodide (0.08 mL, 1.278 mmol) was added to a solution of 002C (80mg, 0.256 mmol) in 5 mL of ACN and the mixture was stirred for 3 hr at80° C. The reaction mixture was cooled to RT and concentrated in vacuo.The crude 068A was used directly in the next step. MS calcd: (M)⁺=328.MS found: (M)⁺=328.

Sodium borohydride (42 mg, 1.1 mmol) was added to a solution of 068A (90mg, 0.275 mmol) in MeOH (6 mL) at RT with constant stirring. Thereaction mixture was stirred overnight at 80° C. The reaction wasquenched with water (20 mL) and extracted with EtOAc (3×20 mL). Theorganic layers were combined, dried over anhydrous Na₂SO₄, andconcentrated to obtain the product as brown oil, which was purified bycolumn chromatography (silica gel, 0-10% MeOH in CH₂Cl₂) to yield 068B.MS calcd: (M+H)⁺=332. MS found: (M+H)⁺=332.

A solution of 068B (496 mg, 1.5 mmol) in dry THF (10 mL) was addeddropwise at −77° C. under N₂ to 2 M LDA in THF/heptane/ethylbenzene (1.5mL) maintaining an internal temperature <−70° C. The stirring wascontinued at −77° C. for 2.5 hr. A solution of iodine (1.6 g) in dry THF(2 mL) was added dropwise to the stirred reaction mixture maintaining aninternal temperature <−70° C. After stirring under N₂ at −77° C. for 1.5hr, the reaction was quenched by addition of saturated NH₄Cl solutionand warmed to 0° C. The mixture was diluted with 5% sodium thiosulfatesolution, then the organic phase was separated and the aqueous phase wasextracted with EtOAc. The combined organic phases were dried (Na₂SO₄),filtered, and evaporated. The product was dried to give 068C. MS calcd:(M+H)⁺=458. MS found: (M+H)⁺=458.

To a 25 mL round bottom flask under N₂, 068C (1 eq.), copper iodide(0.15 eq.) and Pd(dppf)Cl₂ (0.05 eq.) were added. DMF, TEA (4 eq.), and3,3-dimethyl-but-1-yne (3 eq.) were added and the reaction mixturestirred at 60° C. for 2 hr under N₂. The reaction mixture was filteredover Celite® and washed with EtOAc. The solution was diluted with waterand extracted (2×) with EtOAc. The organic phases were combined andwashed with water (2×). The organic layer was separated, dried (Na₂SO₄),evaporated, and purified by column chromatography to give 068D. MScalcd: (M+H)⁺=412. MS found: (M+H)⁺=412.

068D (20 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated in hexane and washedmore with hexane. The powder of 068 was obtained after lyophilization.MS calcd: (M+H)⁺=398. MS found: (M+H)⁺=398.

Example 693-[1-Methyl-5-(4-methyl-cyclohex-1-enyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(thiazole-2-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid

069 was prepared by the same method as 013, using intermediate 068Cinstead of 002G. MS calcd: (M+H)⁺=520. MS found: (M+H)⁺=520.

Example 763-[5-(4-Methyl-cyclohexyl)-1-(3-phenyl-propanoyl)-1,2,3,6-tetrahydropyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

076 was prepared by the same method as 071, using 3-phenylpropanoylchloride instead of acetyl chloride. MS calcd: (M+H)⁺=514. MS found:(M+H)⁺=514.

Example 773-[1-Butyryl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

077 was prepared by the same method as 071, using butyryl chlorideinstead of acetyl chloride. MS calcd: (M+H)⁺=452. MS found: (M+H)⁺=452.

Example 803-[5-(4-Methyl-cyclohexyl)-1-(4-phenyl-butyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

080 was prepared by the same method as 001, using 5-bromo-4-phenylbutaneinstead of methyl iodide. The hydrolysis reaction was conducted asdescribed for 071. MS calcd: (M+H)⁺=514. MS found: (M+H)⁺=514.

Example 813-[1-(2-Hydroxy-ethyl)-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

001H was dissolved in ACN (5 mL) and treated with ethyl bromoacetate(0.025 mL, 0.27 mmol). The resultant mixture was stirred at 80° C. over12 hr, followed by cooling to RT, and concentrating in vacuo. The crudeproduct was dissolved in MeOH (10 mL) and treated with sodiumborohydride (0.80 g, 2.2 mmol) under constant stiffing. The reactionmixture was continued to stir at 80° C. overnight, quenched with water(20 mL), and extracted into EtOAc (3×20 mL). The combined organic layerswere dried over anhydrous Na₂SO₄, and concentrated to obtain a crudeintermediate methyl ester as a brown oil. The ester intermediate waspurified by flash chromatography (silica gel, 0-5% MeOH in methylenechloride) to yield pure methyl ester. The hydrolysis of the ester wasconducted according to the procedure described for 171 to afford 081. MScalcd: (M+H)⁺=426. MS found: (M+H)⁺=426.

Example 833-[1-(2-Carboxy-ethyl)-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

083 was prepared by the same method as 001, usingethyl-3-bromopropionate instead of methyl iodide. The hydrolysisreaction was conducted as described for 071. MS calcd: (M+H)⁺=454. MSfound: (M+H)⁺=454.

Example 843-[1-Carbamoyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

084 was prepared by the same method as 071, using TMS-isocyanate insteadof acetyl chloride. MS calcd: (M+H)⁺: 425. MS found: (M+H)⁺=425.

Example 853-[1-Ethylcarbamoyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

085 was prepared by the same method as 071, using ethyl isocyanateinstead of acetyl chloride. MS calcd: (M+H)⁺=453. MS found: (M+H)⁺=453.

Example 863-[1-(4-Chloro-benzyl)-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

086 was prepared by the same method as 071, using p-chloro-benzylbromideinstead of acetyl chloride. MS calcd: (M+H)⁺=506. MS found: (M+H)⁺=506.

Example 873-[5-(4-Methyl-cyclohexyl)-1-pyridin-2-ylmethyl-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

A solution of 40X (20 mg, 0.05 mmol) was dissolved in methylene chloride(6 mL), cooled to 0° C., and treated with pyridine-1-carboxaldehyde(6.27 mg, 0.055 mmol), TEA (0.007 mL, 0.05 mmol), and sodiumtriacetoxyborohydride (20 mg, 0.10 mmol). The resultant reaction mixturewas warmed to RT, and stirred overnight. The reaction mixture wasconcentrated and purified by prep-TLC (silica gel, 50% EtOAc in hexane)to afford an intermediate methyl ester. Hydrolysis was conducted asdescribed according to procedure for 071. MS calcd: (M+H)⁺=473. MSfound: (M+H)⁺=473.

Example 883-[1-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

088 was prepared by the same method as 087, using 88e from the schemeset forth below instead of pyridine-1-carboxaldehyde. MS calcd:(M+H)⁺=542. MS found: (M+H)⁺=542.

A mixture of glycolic acid (26.2 g, 345 mmol) and water (10 mL) wastreated with aminoguanidine bicarbonate (23.5 g, 172 mmol) in smallportions over a period of 0.1 hr. The resultant mixture was gentlyheated to maintain an internal temp of 25° C. during the addition. Themixture was then treated with slow addition of conc. nitric acid (1.0mL), followed by heating to an internal temperature of 104-108° C. over22 hr. The heating was then discontinued and the solution allowed tocool with stirring. The resultant slurry was cooled down 10° C., stirredover 2 hr, filtered, and rinsed with EtOH. The solids were driedovernight in a vacuum to provide the product 88a as a glycolic acid salt(29.5 g, 85%). MS calcd: (M+H)⁺=115. MS found: (M+H)⁺=115.

A 100 mL flask was charged with glycolate salt of 88a (25.0 g, 130mmol), 1,1,3,3-tetramethoxypropane (26.0 g, 200 mmol), acetic acid (100mL), and EtOH (20 mL). The resultant mixture was heated to a reflux over1 hr, cooled to RT, diluted with DCM (250 mL) and treated with Celite(2.5 g). The mixture then stirred for 1 hr, filtered through a Buchnerfunnel packed with Celite, and rinsed with EtOH. The resultant solutionwas distilled to 5 vols, then cooled to 0° C. over 2 hr. The slurry wasfiltered and the cake was rinsed with cool EtOH. The solids were driedto provide the product 88b (6.1 g, 46%). MS calcd: (M+H)⁺=151. MS found:(M+H)⁺=151.

Compound 88b (1.50 g, 10.0 mmol) was dissolved in CH₂Cl₂ (50 mL), andthe resultant solution was treated with iodobenzene diacetate (3.54 g,11 mmol), followed by the addition of(2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO; 230 mg, 0.015 mmol). Theresultant mixture was warmed to RT and stirred. MTBE (50 mL) was slowlycharged to the reactor, causing the product to precipitate, and theslurry was stirred for 0.5 hr. The reaction mixture was filtered, washedtwice with 1:1DCM/MTBE, and dried in a vacuum overnight to yield theproduct 88c (1.38 g, 89%). MS calcd: (M+H)⁺=149. MS found: (M+H)⁺=149.

88a glycolic acid salt (10.0 g, 52.6 mmol) was dissolved in EtOH (120mL), and the resultant solution was treated with pentane-2,4-dione (6mL, 57.8 mmol) and acetic acid (1.0 mL). The mixture was heated toreflux for 1 hr, then cooled to RT, and diluted with DCM (25 mL),followed by addition of Celite (2.5 g). After stirring for 1 hr, themixture was filtered through a Buchner funnel packed with Celite andrinsed with EtOH. The solution was distilled to 5 vols, then cooled to0° C. for 1-2 hr. The slurry was filtered and the cake was rinsed withcool EtOH. The solids were dried to provide the product 88d (13.0 g,82%). MS calcd: (M+H)⁺=179. MS found: (M+H)⁺=179.

A 50 mL reactor was sequentially charged with CH₂Cl₂ (10 mL), 88d (6.80g, 38 mmol), and iodobenzene diacetate (13.5 g, 42 mmol). Upondissolution of the iodobenzene diacetate, TEMPO (437 mg, 2.8 mmol) wasadded in a single portion, and the resultant mixture was warmed to RT.The reaction was stirred for a short time and treated with MTBE (10 mL).The precipitated product was stirred for an additional 0.5 hr. Thereaction mixture was filtered, washed twice with 1:1 DCM:MTBE, and driedin a vacuum overnight to yield the product 88e (5.5 g, 79%). MS calcd:(M+H)⁺=177. MS found: (M+H)⁺=177.

Compound 88e (1.30 g, 7.5 mmol) was dissolved in THF (75 mL) and theresultant solution was treated with (ethoxycarbonyl methylene)triphenylphosphorane (2.60 g, 15 mmol). The reaction mixture was stirredfor 3 hr. The solvent was evaporated in vacuo and the crude productpurified by column chromatography over silica (DCM, 5% MeOH) to give theproduct 88f. MS calcd: (M+H)⁺=247. MS found: (M+H)⁺=247.

Compound 88f (200 mg, 0.257 mmol) was dissolved in MeOH (50 mL) and theresultant mixture was treated with 10% Pd/C (50 mg). Hydrogenation under50 psi H₂ was run for 48 hr, followed by filtration and concentration togive the product 88g (200 mg, 99%). MS calcd: (M+H)⁺=249. MS found:(M+H)⁺=249.

Compound 88g (0.246 g, 1 mmol) was dissolved in THF (75 mL), and theresultant solution cooled to −78° C. and treated with 1 Mdiisobutylaluminum hydride (DIBAL-H) in hexane (1.0 mL, 1.0 mmol). Thereaction mixture was stirred at −78° C. for 3 hr, quenched withsaturated citric acid (20 mL), and extracted with EtOAc (3×20 mL). Theorganic layers were combined, dried over anhydrous Na₂SO₄, andconcentrated to obtain a crude product as a brown oil. Purification bycolumn chromatography afforded the product 88h. MS calcd: (M+H)⁺=205. MSfound: (M+H)⁺=205.

Example 893-[5-(4-Methyl-cyclohexyl)-1-pyridin-3-ylmethyl-1,2,3,6-tetrahydro-pyridin-4-yl-]-5-phenyl-thiophene-2-carboxylicacid

089 was prepared by the same method as 087, usingpyridine-2-carboxaldehyde instead of pyridine-1-carboxaldehyde. MScalcd: (M+H)⁺=473. MS found: (M+H)⁺=473.

Example 913-[1-[3-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-propyl]-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

091 was prepared by the same method as 087, using 88h instead ofpyridine-1-carboxaldehyde. MS calcd: (M+H)⁺: 570. MS found: (M+H)⁺=570.

Example 923-[5-(4-Methyl-cyclohexyl)-1-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

The glycolate salt of 88a (25.0 g, 130 mmol), was dissolved in EtOH (20mL) and treated with 1,1,3,3-tetramethoxypropane (26.0 g, 200 mmol),followed by acetic acid (100 mL). The resultant mixture was heated to aslight reflux over 1 hr, and the resulting solution was cooled to RT,then diluted with methylene chloride (250 mL) and treated with Celite(2.5 g). The resultant mixture was stirred for 1 hr, filtered through aBuchner funnel packed with Celite, and rinsed with EtOH. The solutionwas distilled to 5 vols, then cooled to 0° C. for 1-2 hr. The slurry wasfiltered and the cake was rinsed with cool EtOH. The solids were driedto provide an intermediate alcohol. This alcohol (60 mg, 0.4 mmol) wasdissolved in methylene chloride (10 mL) and treated with iodobenzenediacetate (142 mg, 44 mmol). Upon dissolution of iodobenzene diacetate,the resultant mixture was treated with TEMPO (9 mg, 0.06 mmol) by asingle charge, and the resultant mixture was allowed to warm to RT. MTBE(10 mL) was slowly added to the reaction mixture, and the resultantslurry stirred for 0.5 hr, then filtered, washed twice with1:1dichloromethane/MTBE, and dried in a vacuum overnight to yield thedesired intermediate aldehyde 88c (54 mg, 91%). The final was preparedaccording to a procedure described for 087, using 88c instead ofpyridine-1-carboxaldehyde. MS calcd: (M+H)⁺=514. MS found: (M+H)⁺=514.

Example 933-[5-(4-Methyl-cyclohexyl)-1-(2-pyridin-4-yl-acetyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

4-Pyridylacetic acid hydrochloride (12 mg, 0.05 mmol) was dissolved inmethylene chloride (6 mL), cooled to 0° C., and treated with TEA (0.021mL, 0.15 mmol) and isobutyl chloroformate (0.008 mL, 0.06 mmol). To theresultant mixture was added 40X (20 mg, 0.05 mmol) over 1 hr withconstant stirring. The mixture was stirred overnight, concentrated andpurified by prep-TLC (silica gel, 50% EtOAc in hexane) to afford anintermediate methyl ester. Hydrolysis was conducted as described for071. MS calcd: (M+H)⁺=501. MS found: (M+H)⁺=501.

Example 953-[5-(4-Methyl-cyclohexyl)-1-(1-methyl-1H-indol-3-ylmethyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

40X (10 mg, 0.025 mmol) was dissolved in methylene chloride (3 mL),cooled to 0° C., and treated with 1-methylindole-3-carboxaldehyde (5 mg,0.03 mmol), TEA (0.007 mL, 0.05 mmol), and sodium triacetoxyborohydride(10 mg, 0.05 mmol). The resultant reaction mixture was warmed to RT, andstirred overnight. The reaction mixture was concentrated and purified byprep-TLC (silica gel, 50% EtOAc in hexane) to afford an intermediatemethyl ester. The hydrolysis reaction was conducted as described for071. MS calcd: (M+H)⁺: 525. MS found: (M+H)⁺=525.

Example 963-[5-(4-Methyl-cyclohexyl)-1-(2-naphthalen-2-yl-acetyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

096 was prepared by the same method as 095, using 2-naphthalene aceticacid instead of 1-methylindole-3-carboxaldehyde. MS calcd: (M+H)⁺=550.MS found: (M+H)⁺=550.

Example 983-[5-(4-Methyl-cyclohexyl)-1-(1-methyl-1H-indole-3-carbonyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

098 was prepared by the same method as 093, using1-methylindole-3-carboxylic acid instead of 4-pyridylacetic acid. MScalcd: (M+H)⁺=539. MS found: (M+H)⁺=539.

Example 1003-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid ethyl ester

A solution of 013 (20 mg, 0.038 mmol) in DCM (4 mL) was treated withEtOH (50 mg), EDC (15 mg, 0.8 mmol) and dimethylaminopyridine (DMAP; 97mg, 0.8 mmol). The reaction was stirred at RT for 10 hr. DCM and NaHCO₃(aq) were added and the organic layer was washed with water and brine,dried, and evaporated to a residue that was purified by silica gelcolumn chromatography using CH₂Cl₂:MeOH as eluent to provide pure 100.MS calcd: (M+H)⁺=550. MS found: (M+H)⁺=550.

Example 1013-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid 2,2-dimethyl-propionyloxymethyl ester

To a solution of 013 (16 mg, 0.03 mmol, 1 equiv) in dry DMF (2 mL) underN₂ atmosphere were added cesium carbonate (29 mg, 0.09 mmol, 3 eq.) andpivaloyloxymethyl chloride (0.013 mL, 0.09 mmol, 3 equiv). Thesuspension was stirred at RT for 3 hr. The reaction mixture wasconcentrated and the resulting residue was purified by columnchromatography to yield pure 101. MS calcd: (M+H)⁺=636. MS found:(M+H)⁺=636.

Example 1023-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid acetoxymethyl ester

102 was prepared by the same method as 101, using bromomethyl acetateinstead of pivaloyloxymethyl chloride. MS calcd: (M+H)⁺=594. MS found:(M+H)⁺=594.

Example 1033-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid 2-dimethylamino-ethyl ester

To a solution of 002 (89 mg, 0.2 mmol) in DMF (3.0 ML) were added HATU(76 mg, 0.2 mmol), 2-dimethylaminoethanol (0.37 mmol), and DMAP (0.15mmol). The reaction mixture was stirred, at RT for 2 hr, andconcentrated under reduced pressure. To the residue was added water, andthis was extracted with EtOAc. The organic phase was dried overanhydrous Na₂SO₄ and evaporated under reduced pressure. The crudeproduct was purified by chromatography on a silica gel column to give103A.

103 was prepared by the same method as 013A, using 103A instead of 002G.MS calcd: (M+H)⁺=593. MS found: (M+H)⁺=593.

Example 1043-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid 1-ethoxycarbonyloxy-ethyl ester

104 was prepared by the same method as 101, using 1-chloroethyl ethylcarbonate instead of pivaloyloxymethyl chloride. MS calcd: (M+H)⁺=638.MS found: (M+H)⁺=638.

Example 1083-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester

108 was prepared by the same method as 101, using4-chloromethyl-5-methyl-1,3-dioxol-2-one instead of pivaloyloxymethylchloride. MS calcd: (M+H)⁺=634. MS found: (M+H)⁺=634.

Example 1093-[1-Methyl-5-(4-methyl-cyclohex-1-enyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

109A was prepared by the same method as 001I, using 001G instead of001H.

109B was prepared by the same method as 001j, using 109A instead of001I.

109 was then prepared by the same method as 001, using 109B instead of001J. MS calcd: (M+H)⁺=394. MS found: (M+H)⁺=394.

Example 1103-[5-(4-Methyl-cyclohexyl)-1-(4-phenyl-propyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

110 was prepared by the same method as 001, using3-bromo-1-phenylpropane instead of methyl iodide. The hydrolysisreaction was conducted as described for 071.

Example 1115-(3,3-Dimethyl-but-1-ynyl)-3-[4-(4-methyl-cyclohexyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-thiophene-2-carboxylicacid

To a mixture of 3-bromopyridine-4-boronic acid (10 mmol) and 001B (20mmol) in DMF (50 mL) and water (15 mL) were added Pd(dppf)Cl₂ (0.5mmol), and Na₂CO₃ (30 mmol) under N₂ and the resulting mixture wasstirred at 80° C. until LCMS showed total consumption of3-bromopyridine-4-boronic acid (3 hr under these condition). Thereaction was cooled to RT, and to it was added water (30 mL) and EtOAc(100 mL). The layers were separated and the aqueous layer isback-extracted with EtOAc (50 mL). The combined organic layers werewashed with water (2×30 mL) brine (30 mL), dried over anhydrous Na₂SO₄,filtered over Celite®, and concentrated under reduced pressure. Theresidue was purified by flash chromatography (silica gel) eluting with0-50% EtOAc in hexanes to give 111A.

To solution of 111A (10 mmol) in THF (50 mL) at −78° C. was added n-BuLi(12 mmol). After stirring for 30 min, triisopropyl borate (15 mmol) wasadded to the reaction mixture. The reaction was allowed to warm to RTover 2 hr, and to it was added saturated aqueous NaH₂PO₄ (10 mL). Theresulting mixture was stirred at RT for 30 min, and then diluted withEtOAc (50 mL). The organic layer was separated, and the aqueous layerwas extracted with EtOAc (50 mL). The combined organic layers werewashed with brine (30 mL), dried over Na₂SO₄, filtered, and concentratedto give 111B, which was used without further purification.

To a mixture of 002A (10 mmol) and 111B (10 mmol) in DMF (50 mL) andwater (15 mL) were added Pd(dppf)Cl₂ (0.5 mmol), and Na₂CO₃ (30 mmol)under N₂ and the resulting mixture was stirred at 80° C. for 2 hr. Thereaction was cooled to RT, and to it was added water (30 mL) and EtOAc(50 mL). The layers were separated and the aqueous layer isback-extracted with EtOAc (50 mL). The combined organic layers werewashed with water (2×20 mL), brine (20 mL), dried over anhydrous Na₂SO₄,filtered over Celite®, and concentrated under reduced pressure. Theresidue was purified by flash chromatography (silica gel) eluting with0-50% EtOAc in hexanes to give 111C.

A mixture of 111C (10 mmol) and Pd-C (10%, wet, 200 mg) in MeOH (50 mL)was hydrogenated with a Parr Shaker under 50 psi H₂ for 15 hr. Themixture was filtered through Celite®, and concentrated to give 111D.

Methyl iodide (20 mmol) was added to a solution of 111D (5 mmol) in 20mL of ACN and the mixture was stirred for 3 hr at 80° C. The reactionmixture was cooled to RT and concentrated to give crude 111E. Crude 111E(5 mmol) was dissolved in MeOH (20 mL) at RT, and to it was added NaBH₄(10 mmol). The reaction was monitored by LCMS, and more NaBH₄ (3 mmoleach time) was added to the reaction in 1-hour intervals until 111E wastotally consumed. The reaction mixture was quenched with water (20 mL)and extracted with EtOAc (3×50 mL). The organic layers were combined,dried over anhydrous Na₂SO₄, and concentrated to obtain the product asbrown oil, which was purified by column chromatography (silica gel,0-10% MeOH in CH₂Cl₂) to yield 111F.

To a solution of 111F (3 mmol) in THF (10 mL) at −78° C. under N₂ wasadded dropwise 2.0 M LDA in THF/heptane/ethylbenzene (3 mL). Thestirring was continued at −78° C. for 2.5 hr. A solution of iodine (2.3g) in dry THF (5 mL) was added dropwise to the reaction mixture. Afterstirring at −78° C. for 1.5 hr, the reaction mixture was quenched withsaturated NH₄Cl solution and warmed to 0° C. The mixture was dilutedwith 5% Na₂S₂O₃ solution, then the organic phase was separated and theaqueous phase was extracted with EtOAc (50 mL). The combined organicphases were dried (Na₂SO₄), filtered, and evaporated. The residue waspurified by column chromatography (silica gel, 0-10% MeOH in CH₂Cl₂) togive 111G.

111G (3.0 mmol) in DCE (15 mL) was treated with1-chloroethylchloroformate (3.6 mmol), and the mixture was stirred underreflux for 4 hr. MeOH (2 mL) was then added to the reaction mixture insmall portions and the heating was continued for an additional 2 hr. Themixture was allowed to cool to RT and concentrated to afford a crude111H, which was used without purification.

To a mixture of 111H (0.1 mmol), copper iodide (0.02 mmol) andPd(dppf)Cl₂ (0.01 mmol) under N₂ were added DMF (2 mL), TEA (0.5 mL),and 3,3-dimethyl-but-1-yne (0.5 mmol). The reaction mixture was stirredat 60° C. for 2 hr under N₂, then filtered over Celite® and rinsed withEtOAc. The solution was diluted with water (20 mL) and extracted (2×30mL) with EtOAc. The organic phases were combined, washed with water(2×15 mL), dried (Na₂SO₄), evaporated, and purified by columnchromatography (0-15%) MeOH in DCM to give 111I.

111I (30 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thento it were added saturated NaH₂PO₄ (3 mL), water (3 mL), and EtOAc (30mL). The organic layer was separated, washed with water (5 mL), driedwith Na₂SO₄, and concentrated to give 111. MS calcd: (M+H)⁺=386. MSfound: (M+H)⁺=386.

Example 1125-(3,3-Dimethyl-but-1-ynyl)-3-[1-methyl-4-(4-methyl-cyclohexyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-thiophene-2-carboxylicacid

112 was prepared by the same method as 003, using 111G instead of 002G.MS calcd: (M+H)⁺=400. MS found: (M+H)⁺=400.

Example 1135-(3,3-Dimethyl-but-1-ynyl)-3-[1-(2-hydroxy-ethyl)-4-(4-methyl-cyclohexyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-thiophene-2-carboxylicacid

To a solution of 111I (50 mg) in DCE (2 mL) was added(tert-butyldimethylsilyloxy)-acetaldehyde, activated molecule sieves 4Apowder (100 mg), and sodium triacetoxyborohydride (100 mg). After thereaction was stirred at RT for 2 hr, the reaction mixture was filteredthrough Celite®, and rinsed with THF (5 mL). The filtrate was treatedwith tetrabutylammonium fluoride (20 mg) and KF (100 mg, powder). Afterthe mixture was stirred at RT overnight, it was filtered throughCelite®, rinsed with DCM/MeOH (5:1), and concentrated. Purification andsubsequent hydrolysis of the intermediate ester, and extraction torecover the resulting acid were conducted generally as described for112, to give 113. MS calcd: (M+H)⁺=430. MS found: (M+H)⁺=430.

Example 1145-(3,3-Dimethyl-but-1-ynyl)-3-[1-(3-hydroxy-propyl)-4-(4-methyl-cyclohexyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-thiophene-2-carboxylicacid

114 is prepared by the same method as 117, using3-(tert-butyldimethylsilyloxy)-1-propanal instead oftetrahydrofuran-3-carboxaldehyde. MS calcd: (M+H)⁺=444. MS found:(M+H)⁺=444.

Example 1165-(3,3-Dimethyl-but-1-ynyl)-3-[4-(4-methyl-cyclohexyl)-1-(tetrahydro-furan-3-yl)-1,2,5,6-tetrahydro-pyridin-3-yl]-thiophene-2-carboxylicacid

To a solution of 111I (50 mg) in DCE (2 mL) is addeddihydrofuran-3(2H)-one (100 mg), activated molecule sieves 4A powder(100 mg), and sodium triacetoxyborohydride (100 mg). The reaction isstirred at RT for 15 hr, the mixture is filtered through Celite®, rinsedwith EtOAc (20 mL), and concentrated. Purification and subsequenthydrolysis of the intermediate ester, and extraction to recover theresulting acid, are conducted generally as described for 112, to give116.

Example 1175-(3,3-Dimethyl-but-1-ynyl)-3-[4-(4-methyl-cyclohexyl)-1-(tetrahydro-furan-3-ylmethyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-thiophene-2-carboxylicacid

To a solution of 111H (50 mg) in DCE (2 mL) were addedtetrahydrofuran-3-carboxaldehyde (100 mg), and sodiumtriacetoxyborohydride (100 mg). The reaction was stirred at RT for 15hr, and the mixture was filtered through Celite®, rinsed with EtOAc (20mL), and concentrated to give 117A.

To a mixture of 117A (0.1 mmol), copper iodide (0.02 mmol) andPd(dppf)Cl₂ (0.01 mmol) under N₂ were added DMF (2 mL), TEA (0.5 mL),and 3,3-dimethyl-but-1-yne (0.5 mmol). The reaction mixture was stirredat 60° C. for 2 hr under N₂. The reaction mixture was filtered overCelite® and rinsed with EtOAc. The solution was diluted with water (20mL) and extracted (2×30 mL) with EtOAc. The organic phases werecombined, washed with water (2×15 mL), dried (Na₂SO₄), evaporated, andpurified by column chromatography (0-15%) MeOH in DCM to give 117B.

117B (30 mg) was dissolved in THF (2 mL), water (1 mL), and MeOH (1 mL).LiOH (2 M, 0.5 mL) was then added. The reaction was stirred at RT for 5hr, and then water (1 mL), and EtOAc (3 mL) were added. The organiclayer was separated, concentrated, and lyophilized to give 117. MScalcd: (M+H)⁺=470. MS found: (M+H)⁺=470.

Example 1195-(3,3-Dimethyl-but-1-ynyl)-3-[4-(4-methyl-cyclohexyl)-1-(tetrahydro-furan-3-carbonyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-thiophene-2-carboxylicacid

To a solution of 111I (50 mg) in DCM (2 mL) is addedtetrahydrofuan-3-carboxylic acid (0.2 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI; 0.3 mmol), TEA(0.05 mL) and DMAP (5 mg). The reaction is stirred at RT for 15 hr, andthe mixture is diluted with EtOAc (205 mL), washed with water (2×10 mL)and brine (10 mL), dried over MgSO₄, and concentrated. Purification andsubsequent hydrolysis of the intermediate ester, and extraction torecover the resulting acid are conducted generally as described for 112,to give 119.

Example 1205-(3,3-Dimethyl-but-1-ynyl)-3-[1-(3-hydroxy-cyclopentanecarbonyl)-4-(4-methyl-cyclohexyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-thiophene-2-carboxylicacid

To a solution of 111I (50 mg) in DCM (2 mL) is added3-oxo-1-cyclopentanecarboxylic acid (0.2 mmol), EDCI (0.3 mmol), TEA(0.05 mL) and DMAP (5 mg). After the reaction is stirred at RT for 15hr, the reaction mixture is diluted with MeOH (1 mL). NaBH₄ (1 mmol) isadded, and the mixture stirred until the reduction of ketone is complete(about 30 min). The mixture is diluted with acetone (1 mL) and EtOAc (40mL), washed with water (2×10 mL) and brine (10 mL), dried over MgSO₄,and concentrated. Purification and subsequent hydrolysis of theintermediate ester, and extraction to recover the resulting acid, areconducted generally as described for 112, to give 120.

Example 1215-(3,3-Dimethyl-but-1-ynyl)-3-[4-(4-methyl-cyclohexyl)-1-(tetrahydro-furan-3-sulfonyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-thiophene-2-carboxylicacid

To a solution of 111I (50 mg) in DCM (2 mL) is addedtetrahydrofuan-3-sulfonyl chloride (0.2 mmol) and TEA (0.5 mmol). Themixture is stirred for 1 hr, and then treated with aqueous Na₂CO₃ (1 M,0.5 mL). After stiffing is continued for 10 min, the mixture is dilutedwith EtOAc (40 mL), washed with water (2×10 mL) and brine (10 mL), driedover MgSO₄, and concentrated. Purification and subsequent hydrolysis ofthe intermediate ester, and extraction to recover the resulting acid,are conducted generally as described for 112, to give 121.

Example 1223-[4-(4-Methyl-cyclohexyl)-1-(tetrahydro-furan-3-carbonyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid

To a solution of 111H (50 mg) in DCM (2 mL) is addedtetrahydrofuan-3-carboxylic acid (0.2 mmol), EDCI (0.3 mmol), TEA (0.05mL) and DMAP (5 mg). The reaction is stirred at RT for 15 hr, themixture is diluted with EtOAc (50 mL), washed with water (2×10 mL) andbrine (10 mL), dried over MgSO₄, and concentrated. The residue ispurified by column chromatography with 0-10% MeOH in DCM to give theester 122A.

A mixture of 122A,[4-({[(1,1-dimethylethyl)oxy]-carbonyl}amino)phenyl]boronic acid (0.2mmol), Pd(dppf)Cl₂ (0.01 mmol), and Na₂CO₃ (0.3 mmol) in DMF (2 mL) andH₂O (0.5 mL) under N₂ is stirred at 92° C. for 4 hr. The reaction isdiluted with EtOAc (50 mL), washed with water (2×10 mL) and brine (10mL), dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. The residue is purified by flash chromatography (silica gel),eluting with 0-5% MeOH in CH₂Cl₂ to give 122B.

122B is stirred in DCM (3 mL) and trifluoroacetic acid (TFA, 1 mL) at RTunder N₂ for 1 hr. The reaction is evaporated in vacuo. The residue isdissolved in DMF (2 mL), and to it is added HATU (0.2 mmol), TEA (0.5mmol), and 1,3-thiazole-4-carboxylic acid (0.2 mmol). After the reactionis stirred at RT for 15 hr, the mixture is diluted with EtOAc (50 mL),washed with water (2×10 mL) and brine (10 mL), dried over MgSO₄, andconcentrated. The residue is purified by column chromatography with0-10% MeOH in DCM to give ester 122C. Purification and subsequenthydrolysis of 122C, and extraction to recover the resulting acid, areconducted generally as described for 112, to give 122.

Example 1233-[4-(4-Methyl-cyclohexyl)-1-(tetrahydro-furan-3-carbonyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-5-(4-pyrazolo[1,5-a]pyrimidin-2-yl-phenyl)-thiophene-2-carboxylicacid

123A is prepared by the same method as 122B, using 005B instead of[4-({[(1,1-dimethylethyl)oxy]-carbonyl}amino)phenyl]boronic acid in thereaction with 122A. Hydrolysis of the methyl ester intermediate, andextraction to recover the resulting acid, are conducted generally asdescribed for 112, to give 123.

Example 1245-(3,3-Dimethyl-but-1-ynyl)-3-[1-(2-fluoro-ethyl)-4-(4-methyl-cyclohexyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-thiophene-2-carboxylicacid

124 was prepared by the same method as 117, using 1-bromo-2-fluoroethanewith DIEA instead of tetrahydrofuran-3-carboxaldehyde. MS calcd:(M+H)⁺=432. MS found: (M+H)⁺=432.

Example 1253-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid phenyl ester

125 was prepared by the same method as 100, using phenol instead ofEtOH. MS calcd: (M+H)⁺=598. MS found: (M+H)⁺=598.

Example 1263-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid cyclohexyloxycarbonyl-oxymethyl ester

126 was prepared by the same method as 101, using 1-chloromethylcyclohexyl carbonate instead of pivaloyloxymethyl chloride. MS calcd:(M+H)⁺=678. MS found: (M+H)⁺=678.

Example 1275-(3,3-Dimethyl-but-1-ynyl)-3-[5-(4-methyl-cyclohexyl)-1-pyridin-2-ylmethyl-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

Intermediate 002G (0.29 g, 0.623 mmol) was dissolved in dichloroethane(10 mL) and was treated with 1-chloroethyl chloroformate (0.086 mL,0.795 mmol), followed by DIPEA (0.138 mL, 0.795 mmol) with stiffingunder argon. After 20 hr, the reaction mixture was evaporated underreduced pressure and the resulting brown foam was dissolved in MeOH (20mL), and heated to reflux with stirring. After 1 hr, the reactionmixture was evaporated under reduced pressure and the brown oily product127A was directly used in the next step.

To a mixture of 127A (0.05 mmol), copper iodide (0.01 mmol) andPd(dppf)Cl₂ (0.005 mmol) under N₂ were added DMF (2 mL), TEA (0.5 mL),and 3,3-dimethyl-but-1-yne (0.3 mmol). The reaction mixture was stirredat 60° C. for 2 hr under N₂. The reaction mixture was filtered overCelite® and rinsed with EtOAc. The solution was diluted with water (20mL) and extracted (2×30 mL) with EtOAc. The organic phases werecombined, washed with water (2×15 mL), dried (Na₂SO₄), evaporated, andpurified by column chromatography (0-15%) MeOH in DCM to give 127B.

127B (20 mg, 0.04 mmol) was dissolved in dichloroethane (3 mL), andtreated with 2-pyridinecarboxaldehyde (12.3 mg, 0.11 mmol), TEA (0.02mL, 0.15 mmol), and sodium triacetoxyborohydride (30 mg, 0.15 mmol). Thereaction was stirred overnight at RT. The reaction mixture wasconcentrated and purified by prep-TLC (silica gel, 50% EtOAc in hexane)to give an intermediate methyl ester 127C.

127C (20 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated in hexane and washedmore with hexane. The powder of 127 was obtained after lyophilization.MS calcd: (M+H)⁺=477. MS found: (M+H)⁺=477.

Example 1285-(3,3-Dimethyl-but-1-ynyl)-3-[1-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

128 was prepared by the same method as 127, using 88e instead of2-pyridinecarboxaldehyde. MS calcd: (M+H)⁺=546. MS found: (M+H)⁺=546.

Example 1303-[1-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid

A solution of 127A (20 mg, 0.045 mmol) was dissolved in dichloroethane(3 mL), and treated with 88e (19.4 mg, 0.11 mmol), TEA (0.02 mL, 0.15mmol), and sodium triacetoxyborohydride (30 mg, 0.15 mmol). The reactionwas stirred overnight at RT. The reaction mixture was concentrated andpurified by prep-TLC (silica gel, 50% EtOAc in hexane) to give anintermediate 130A.

130 was then prepared by the same method as 013, using 130A instead of002G to give 130B, followed by hydrolysis to give the acid. MS calcd:(M+H)⁺=668. MS found: (M+H)⁺=668.

Example 1313-[5-(4-Methyl-cyclohexyl)-1-pyridin-2-ylmethyl-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid

131 was prepared by the same method as 130, using2-pyridinecarbox-aldehyde instead of 88e. MS calcd: (M+H)⁺=599. MSfound: (M+H)⁺=599.

Example 1325-[4-(7-Amino-pyrazolo[1,5-a]pyrimidin-2-yl)-phenyl]-3-[1-methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid, hydrochloride salt

A mixture of trans-3-(dimethylamino)-acrylonitrile (230 μL, 2.10 mmol)and 5-amino-3-(4-bromophenyl)pyrazole) (500 mg, 2.10 mmol) in aceticacid (8 mL) was stirred at 110° C. for 3 hr, cooled to RT, concentrated,sonicated in saturated NaHCO₃ (10 mL), and filtered. The cake was washedwith water (100 mL) and dried in vacuo to give 132A as a yellow powder(600 mg, 98.8%). MS calcd: (M+H)⁺=290. MS found: (M+H)⁺=290.

132B was prepared by the same method as 005B, using 132A instead of005A. MS calcd: (M+H)⁺=337. MS found: (M+H)⁺=337.

132C was prepared by the same method as 129B, using 132B instead of4-bromophenylboronic acid. MS calcd: (M+H)⁺=542. MS found: (M+H)⁺=542.

132 was then prepared by the same method as 129, using 132C instead of129C. MS calcd: (M+H)⁺=528. MS found: (M+H)⁺=528.

Example 1335-(3,3-Dimethyl-but-1-ynyl)-3-[5-(4-methyl-cyclohexyl)-1-pyridin-4-ylmethyl-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

Compound 133 was prepared by the same method as 127, using4-pyridinecarboxaldehyde instead of 2-pyridinecarboxaldehyde. MS calcd:(M+H)⁺=477. MS found: (M+H)⁺=477.

Example 1345-Cyclopropylethynyl-3-[5-(4-methyl-cyclohexyl)-1-pyridin-2-ylmethyl-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

Compound 134 was prepared by the same method as 127, usingcyclopropylacetylene instead of 3,3-dimethyl-1-butyne. MS calcd:(M+H)⁺=461. MS found: (M+H)⁺=461.

Example 1355-[4-(3a,7a-Dihydro-furo[3,2-b]pyridin-2-yl)-phenyl]-3-[1-methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

135A was prepared by the same method as 129A, using4-bromophenylacetylene instead of trimethylsilylacetylene and2-iodo-3-hydroxypyridine instead of 4-bromothiazole and heating at 90°C. MS calcd: (M+H)⁺=275. MS found: (M+H)⁺=275.

135B was prepared by the same method as 005B, using 135A instead of005A. MS calcd: (M+H)⁺=322. MS found: (M+H)⁺=322.

135C was prepared by the same method as 129B, using 135B instead of4-bromophenylboronic acid. MS calcd: (M+H)⁺=527. MS found: (M+H)⁺=527.

135 was then prepared by the same method as 129, using 135C instead of129C. MS calcd: (M+H)⁺=513. MS found: (M+H)⁺=513.

Example 1363-[1-(5-Chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid

136 was prepared by the same method as 127, using5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde insteadof 2-pyridinecarboxaldehyde. MS calcd: (M+H)⁺=597. MS found: (M+H)⁺=597.

Example 1375-(3,3-Dimethyl-but-1-ynyl)-3-[1-(2-methoxy-ethyl)-4-(4-methyl-cyclohexyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-thiophene-2-carboxylicacid

137 was prepared by the same method as 117, using 2-bromoethyl methylether with DIEA instead of tetrahydrofuran-3-carboxaldehyde. MS calcd:(M+H)⁺=444. MS found: (M+H)⁺=444.

Example 1385-Cyclopropylethynyl-3-[1-(2-hydroxy-ethyl)-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

138A was prepared by the same method as 127B, using cyclopropylacetyleneinstead of tert-butylacetylene.

To a solution of 138A (50 mg) in DCE (2 mL) was added(tert-butyldimethylsilyloxy)-acetaldehyde, activated molecule sieves 4Apowder (100 mg), and sodium triacetoxyborohydride (100 mg). After thereaction was stirred at RT for 2 hr, the reaction mixture was filteredthrough Celite®, and rinsed with THF (5 mL). The filtrate was treatedwith tetrabutylammonium fluoride (20 mg) and KF (100 mg, powder). Afterthe mixture was stirred at RT overnight, it was filtered throughCelite®, rinsed with DCM/MeOH (5/1), and concentrated. The crude productwas purified with preparative TLC, developing with 10% MeOH in DCM togive 138B.

138 was then prepared by the same method as 001, using 138B instead of001j. MS calcd: (M+H)⁺=414. MS found: (M+H)⁺=414.

Example 1395-[4-(3-Methyl-3H-imidazo[4,5-b]pyridin-2-yl)-phenyl]-3-[1-methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

139A was prepared by the same method as 137A, using 2,3-diaminopyridineand 4-iodobenzoic acid instead of 4-bromo-1,2-diaminobenzene andthiazole-4-carboxylic acid. MS calcd: (M+H)⁺=322. MS found: (M+H)⁺=322.

139B was prepared by the same method as 137B, using 139A instead of137A. MS calcd: (M+H)⁺=336. MS found: (M+H)⁺=336.

139C was prepared by the same method as 005B, using bis(neopentylglycolato) diboron and 139B instead of bis(pinacolato) diboron and 005A.MS calcd: (M+H)⁺=322. MS found: (M+H)⁺=322.

139D was prepared by the same method as 129B, using 139C instead of4-bromophenylboronic acid. MS calcd: (M+H)⁺=541. MS found: (M+H)⁺=541.

139 was then prepared by the same method as 129, using 139D instead of129C. MS calcd: (M+H)⁺=527. MS found: (M+H)⁺=527.

Example 1405-[4-(3H-Imidazo[4,5-b]pyridin-2-yl)-phenyl]-3-[1-methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

140A was prepared by the same method as 137B, using 139A and2-(trimethylsilyl)ethoxymethyl chloride instead of iodomethane. MScalcd: (M+H)⁺=452. MS found: (M+H)⁺=452.

140B was prepared by the same method as 005B, using bis(neopentylglycolato) diboron and 140A instead of bis(pinacolato) diboron and 005A.MS calcd: (M+H)⁺=438. MS found: (M+H)⁺=438.

140C was prepared by the same method as 129B, using 140B instead of4-bromophenylboronic acid. MS calcd: (M+H)⁺=657. MS found: (M+H)⁺=657.

140 was then prepared by the same method as 138, using 140C instead of138C to give 140. MS calcd: (M+H)⁺=513. MS found: (M+H)⁺=513.

Example 1413-[5-(4-Methyl-cyclohexyl)-1-pyridin-2-ylmethyl-1,2,3,6-tetrahydro-pyridin-4-yl]-5-(4-pyrazolo[1,5-a]pyrimidin-2-yl-phenyl)-thiophene-2-carboxylicacid

A solution of 127A (20 mg, 0.045 mmol) was dissolved in dichloroethane(3 mL), and treated with 2-pyridinecarboxaldehyde (12.3 mg, 0.11 mmol),TEA (0.02 mL, 0.15 mmol), and sodium triacetoxyborohydride (30 mg, 0.15mmol). The reaction was stirred overnight at RT. The reaction mixturewas concentrated and purified by prep-TLC (silica gel, 50% EtOAc inhexane) to give an intermediate methyl ester 141A.

141A (20 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated to give 141B.

141 was prepared by the same method as 005, using 005B reacted with 141Binstead of 102. MS calcd: (M+H)⁺=590. MS found: (M+H)⁺=590.

Example 1425-(3,3-Dimethyl-but-1-ynyl)-3-[1-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

142 was prepared by the same method as 127, using1,3-dimethyl-1H-pyrazole-4-carbaldehyde instead of2-pyridinecarboxaldehyde. MS calcd: (M+H)⁺=494. MS found: (M+H)⁺=494.

Example 1433-[5-(4-Methyl-cyclohexyl)-1-quinolin-2-ylmethyl-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

143 is prepared by the same method as 087, usingquinoline-2-carboxaldehyde instead of pyridine-1-carboxaldehyde. MScalcd: (M+H)⁺=523. MS found: (M+H)+=523.

Example 1443-[1-(2-Bromo-pyridin-4-ylmethyl)-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

144 was prepared by the same method as 087, using2-bromo-isonicotinaldehyde instead of pyridine-1-carboxaldehyde. MScalcd: (M+H)⁺=552. MS found: (M+H)⁺=552.

Example 1453-[5-(4-Methyl-cyclohexyl)-1-(2-thiophen-2-yl-pyridin-4-ylmethyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

145 was prepared by the same method as 087, using2-(thiophen-2-yl)isonicotinaldehyde instead ofpyridine-1-carboxaldehyde. MS calcd: (M+H)⁺=556. MS found: (M+H)⁺=556.

Example 1463-[1-(3,5-Dichloro-pyridin-4-ylmethyl)-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

146 was prepared by the same method as 087, using3,5-dichloroisonicotinaldehyde instead of pyridine-1-carboxaldehyde. MScalcd: (M+H)⁺=542. MS found: (M+H)⁺=542.

Example 1473-[1-[2-(4-Fluoro-phenyl)-pyridin-4-ylmethyl]-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

147 was prepared by the same method as 087, using2-(4-fluorophenyl)-isonicotinaldehyde instead ofpyridine-1-carboxaldehyde. MS calcd: (M+H)⁺=567. MS found: (M+H)⁺=567.

Example 1513-[1-(5,7-Diisopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

151 was prepared by the same method as 088 using2,6-dimethylheptane-3,5-dione instead of pentane-2,4-dione. MS calcd:(M+H)⁺=598. MS found: (M+H)⁺=598.

Example 1523-[1-(2-Benzoimidazol-1-yl-acetyl)-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

152 was prepared by the same method as 093, using2-(1H-benzo[d]imidazol-1-yl)acetic acid (prepared by reactingbenzimidazole with bromoacetic acid ester, followed by hydrolysis of theester) instead of 4-pyridylacetic acid hydrochloride. MS calcd:(M+H)⁺=540. MS found: (M+H)⁺=540.

Example 1533-[5-(4-Methyl-cyclohexyl)-1-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl-acetyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

153 was prepared by the same method as 093, using2-([1,2,4]triazolo[1,5-a]pyridin-2-yl)acetic acid instead of4-pyridylacetic acid hydrochloride. MS calcd: (M+H)⁺=541. MS found:(M+H)⁺=541.

Example 1543-[5-(4-Methyl-cyclohexyl)-1-(6-trifluoromethyl-pyridine-3-carbonyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

154 was prepared by the same method as 093, using6-(trifluoromethyl)nicotinic acid instead of 4-pyridylacetic acidhydrochloride. MS calcd: (M+H)⁺=555. MS found: (M+H)⁺=555.

Example 1553-[1-(3-Amino-pyrazine-2-carbonyl)-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

155 was prepared by the same method as 093, using3-aminopyrazine-2-carboxylic acid instead of 4-pyridylacetic acidhydrochloride. MS calcd: (M+H)⁺=503. MS found: (M+H)⁺=503.

Example 1563-[5-(4-Methyl-cyclohexyl)-1-(3-methyl-3H-imidazole-4-carbonyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

156 was prepared by the same method as 093, using1-methyl-1H-imidazole-5-carboxylic acid instead of 4-pyridylacetic acidhydrochloride. MS calcd: (M+H)⁺=490. MS found: (M+H)⁺=490.

Example 1583-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-[4-(2-thiazol-4-yl-vinyl)-phenyl]-thiophene-2-carboxylicacid

A mixture of 4-bromobenzyl bromide (1.00 g, 4.00 mmol) andtriphenylphosphine (1.70 g, 6.00 mmol) in toluene (10 mL) was stirred at80° C. overnight. The reaction mixture was concentrated, followed bysonication in hexane, filtration, and a subsequent hexane wash gave awhite solid, which was dried in vacuo. This white solid (906 mg, 1.77mmol) was dissolved in THF (10 mL), cooled to 0° C., and lithiumhexamethyl disilazide (1 M) in THF (1.95 mL, 1.95 mmol) was added. After0.5 hr, thiazole-4-carboxaldehyde (200 mg, 1.77 mmol) was added, the icebath was removed, and the mixture stirred for 0.5 hr. The reactionmixture was quenched by the addition of water, extracted with EtOAc(2×30 mL), the organic layer was washed with brine, dried over MgSO₄,concentrated and filtered through a silica plug using 30%-100%EtOAc/hexane to give 158A as a clear oil. MS calcd: (M+H)⁺=267. MSfound: (M+H)⁺=267.

158B was prepared by the same method as 005B, using 158A instead of005A. MS calcd: (M+H)⁺=314. MS found: (M+H)⁺=314.

158C was prepared by the same method as 129B, using 158B instead of4-bromophenylboronic acid. MS calcd: (M+H)⁺=519. MS found: (M+H)⁺=519.

158 was then prepared by the same method as 129, using 158C instead of129C. MS calcd: (M+H)⁺=505. MS found: (M+H)⁺=505.

Example 1593-[5-(4-Methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid

Thiazole-4-carboxylic acid (1.42 g, 11 mmol) in DCM (20 mL) was treatedwith oxallyl chloride (8 mL, 2 M solution in DCM), followed by 2 dropsof DMF. After 1 hr at RT, solvent was evaporated, and the residue wasredissolved in DCM (20 mL). To the solution was added4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (2.20 g, 10mmol) and TEA (2 mL). After 30 min at RT, the reaction mixture wasdiluted with ether (100 mL), washed with water, sodium bicarbonate, andbrine. The organic layer was dried over anhydrous MgSO₄, filtered andconcentrated to give 159A, which was used without further purification.

159 was then prepared by the same method as 005, using 159A and 127Ainstead of 005B and 002. The coupling product was further hydrolyzedwith LiOH to give 159. MS calcd: (M+H)⁺=508. MS found: (M+H)⁺=508.

Example 1605-{2,5-Difluoro-4-[(thiazole-4-carbonyl)-amino]-phenyl}-3-[1-methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

160 was prepared by the same method as 059, using4-amino-2,5-difluorophenylboronic acid pinacol ester instead of4-amino-3-fluorophenylboronic acid. MS calcd: (M+H)⁺=558. MS found:(M+H)⁺=558.

Example 1615-[4-(5,7-Dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-phenyl]-3-[1-methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

A mixture of acetylacetone (126 mg, 1.26 mmol) and5-amino-3-(4-bromophenyl)pyrazole (300 mg, 1.26 mmol) in EtOH wasrefluxed overnight, concentrated and used for the preparation of 161Bwithout further purification. MS calcd: (M+H)⁺=303. MS found:(M+H)⁺=303.

161B was prepared by the same method as 005B, using 161A instead of005A. MS calcd: (M+H)⁺=350. MS found: (M+H)⁺=350.

161C was prepared by the same method as 129B, using 161B instead of4-bromophenylboronic acid. MS calcd: (M+H)⁺=555. MS found: (M+H)⁺=555.

161 was prepared by the same method as 129, using 161C instead of 129C.MS calcd: (M+H)⁺=541. MS found: (M+H)⁺=541.

Example 1623-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-[4-(7-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-phenyl]-thiophene-2-carboxylicacid

162 was prepared by the same method as 161, using trans4-methoxy-3-buten-2-one instead of acetylacetone to give the titlecompound. MS calcd: (M+H)⁺=527. MS found: (M+H)⁺=527.

Example 1633-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-[4-(6-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-phenyl]-thiophene-2-carboxylicacid

163A was prepared by the same method as 132A, using 3-ethoxymethacroleininstead of trans-3-(dimethylamino)-acrylonitrile. MS calcd: (M+H)⁺=289.MS found: (M+H)⁺=289.

163B was prepared by the same method as 005B, using 163A instead of005A. MS calcd: (M+H)⁺=336. MS found: (M+H)⁺=336.

163C was prepared by the same method as 129B, using 163B instead of4-bromophenylboronic acid. MS calcd: (M+H)⁺=541. MS found: (M+H)⁺=541.

163 was then prepared by the same method as 129, using 163C instead of129C. MS calcd: (M+H)⁺=527. MS found: (M+H)⁺=527.

Example 1645-(4-Imidazo[1,2-b]pyridazin-2-yl-phenyl)-3-[1-methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

A mixture of 3-aminopyridazine (100 mg, 1.05 mmol),2,4′-dibromoacetophenone (146 mg, 0.53 mmol) and NaHCO₃ (133 mg, 1.58mmol) in EtOH (3 mL) was refluxed for 4h. The reaction mixture wasconcentrated, diluted in EtOAc, washed with water, brine, dried overMgSO₄, concentrated and used for the preparation of 164B without furtherpurification. MS calcd: (M+H)⁺=275. MS found: (M+H)⁺=275.

164B was prepared by the same method as 005B, using 164A instead of005A. MS calcd: (M+H)⁺=322. MS found: (M+H)⁺=322.

164C was prepared by the same method as 129B, using 164B instead of4-bromophenylboronic acid. MS calcd: (M+H)⁺=527. MS found: (M+H)⁺=527.

164 was then prepared by the same method as 129, using 164C instead of129C. MS calcd: (M+H)⁺=513. MS found: (M+H)⁺=513.

Example 1653-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-(4-pyrazolo[4,3-b]pyridin-2-yl-phenyl)-thiophene-2-carboxylicacid

165A was prepared by the same method as 129B. MS calcd: (M+H)⁺=489. MSfound: (M+H)⁺=489.

A mixture of 165A (75 mg, 0.15 mmol), pyrazolo[4,3-b]pyridine (110 mg,0.92 mmol), K₃PO₄ (54.3 mg, 0.26 mmol), Cu(I)I (2.4 mg, 0.01 mmol), andtrans-N,N′-dimethylcyclohexane-1,2-diamine (6 μL, 0.04 mmol) in toluene(2 mL) was heated and stirred at 120° C. for 48 hr. The reaction mixturewas diluted in EtOAc, washed with water, brine, dried over MgSO₄,concentrated and purified by prep-TLC using 3:7:1 EtOAc/DCM/MeOH (v/v)to afford 165B. MS calcd: (M+H)⁺=527. MS found: (M+H)⁺=527.

165 was then prepared by the same method as 129, using 165B instead of129C. MS calcd: (M+H)⁺=513. MS found: (M+H)⁺=513.

Example 1665-{3,5-Difluoro-4-[(thiazole-4-carbonyl)-amino]-phenyl}-3-[1-methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

166 was prepared by the same method as 059, using4-amino-3,5-difluorophenylboronic acid pinacol ester instead of4-amino-3-fluorophenylboronic acid. MS calcd: (M+H)⁺=558. MS found:(M+H)⁺=558.

Example 1673-[1-Methyl-4-(4-methyl-cyclohexyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid

167 was prepared by the same method as 013, using 111G instead of 002G.MS calcd: (M+H)⁺=522. MS found: (M+H)⁺=522.

Example 1685-(3,3-Dimethyl-but-1-ynyl)-3-[1-(2-hydroxy-ethyl)-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

168 was prepared by the same method as 117, using2-(tert-butyldimethylsilyloxy)-acetaldehyde instead oftetrahydrofuran-3-carboxaldehyde. MS calcd: (M+H)⁺=430. MS found:(M+H)⁺=430.

Example 1693-[1-Methyl-4-(4-methyl-cyclohexyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-5-(4-pyrazolo[1,5-a]pyrimidin-2-yl-phenyl)-thiophene-2-carboxylicacid

169A was prepared by treatment of 111G (100 mg) with LiOH (saturatedsolution, 0.3 mL) in THF (3 mL). After the reaction mixture was stirredovernight, to the mixture was added phorphoric acid (5 M in water, 0.2mL), and the reaction mixture was diluted with EtOAc (10 mL). The layerswere separated, and the aqueous layer was extracted with EtOAc (10 mL).Combined organic layers were washed with brine (5 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated. The crude 169A was usedwithout further purification.

169 was then prepared by the same method as 005, using 169A instead of002. MS calcd: (M+H)⁺=513. MS found: (M+H)⁺=513.

Example 1705-(3,3-Dimethyl-but-1-ynyl)-3-[1-(2-hydroxy-acetyl)-4-(4-methyl-cyclohexyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-thiophene-2-carboxylicacid

Acetoxyacetic acid (12 mg) was dissolved in DMF (3 mL). To the solutionwere added HATU (38 mg) DIPEA (0.1 mL), and 111H (20 mg). The reactionmixture was stirred at RT for 55 min. The reaction was then diluted withEtOAc (30 mL), washed with water (2×10 mL), dried over anhydrous MgSO₄,and purified by column (eluted with 10-100% EtOAc/hexanes) to givecompound 170A.

Compound 170A was treated with copper iodide (0.15 eq.) TEA (4 eq.),3,3-dimethyl-but-1-yne (3 eq.), and Pd(dppf)Cl₂ (0.05 eq.) in DMF (2mL). The reaction mixture was stirred at 60° C. for 2 hr under N₂. Thereaction mixture was filtered on Celite® and washed with EtOAc. Thefiltrate was diluted with water, and extracted twice with EtOAc. Theorganic phases were combined and washed twice with water. The organiclayer was separated, dried (Na₂SO₄), evaporated, and purified by columnchromatography to give 170B.

Hydrolysis of 170B was performed using LiOH in THF (2 mL) and EtOH (1mL). The reaction was stirred at RT for 6 hr, and then diluted withEtOAc. The organic layer was washed with water and concentrated. Thefinal product was precipitated out in hexane and washed more withhexane. The powder of 170 was obtained with lyophilization. MS calcd:(M+H)⁺=444. MS found: (M+H)⁺=444.

Example 1715-Iodo-3-[4-(4-methyl-cyclohexyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-thiophene-2-carboxylicacid

111H (20 mg) was hydrolyzed with LiOH (30 mg) in solvent of THF, MeOH,and water (2:1:1) for 2 hr. Extraction of the mixture with EtOAc,washing with water, and concentration gave pure product 171. MS calcd:(M+H)⁺=432. MS found: (M+H)⁺=432.

Example 1725-(1-Methyl-cyclopropylethynyl)-3-[1-methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

1.6 M BuLi in hexane (9.04 mL, 14.46 mmol) was slowly added to asolution of (cyclopropylethynyl)trimethylsilane (1.00 g, 7.23 mmol) inethyl ether (10 mL). The reaction mixture was stirred at RT overnight,cooled to −78° C., dimethyl sulfate (0.89 mL, 9.40 mmol) was added, andthe reaction mixture warmed to RT over the course of 1.5 hr. sat. NH₄Clwas added and the reaction mixture was extracted with ethyl ether. Theorganic layer was washed with water, brine, dried over MgSO₄, andconcentrated to afford 172A, which was used for the preparation of 172Bwithout further purification.

A mixture of 172A (50 mg, 0.33 mmol), 068C (50 mg, 0.11 mmol),Pd(dppf)Cl₂ (8 mg, 0.01 mmol), KF (19 mg, 0.33 mmol), Cu(I)I (4 mg, 0.02mmol), and benzyltrimethylammonium chloride (2 mg, 0.01 mmol) in DMF:TEA(1 mL, 1:1, v/v) was stirred at 90° C. for 1 hr. The reaction mixturewas concentrated and purified by prep-TLC using 10% MeOH/DCM to afford172B. MS calcd: (M+H)⁺=412. MS found: (M+H)⁺=412.

172 was prepared by the same method as 129, using 172B instead of 129C.MS calcd: (M+H)⁺=398. MS found: (M+H)⁺=398.

Example 1733-[1-Methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-(1-phenyl-cyclopropylethynyl)-thiophene-2-carboxylicacid

To a solution of 1-phenyl-1-cyclopropanecarboxylic acid (1.18 g, 5.0mmol) in anhydrous ether (10 mL) at 0° C. was added slowly lithiumaluminum hydride solution in THF (1.0 M, 6.0 mL)). The reaction was thenstirred at RT for 2 hr. To the reaction mixture was then added water(0.24 mL), 15% aqueous NaOH (0.24 mL), and water (0.72 mL) whilestirring. The mixture was stirred for 20 min at RT, filtered andconcentrated to give the crude 173A, which was used for the next stepwithout purification.

To a suspension of 173A and molecular sieves (powdered, activated, 4A)in DCM was added PCC (10 mmol). After stirring for 12 hr at RT, thereaction was filtered through silica gel, and concentrated to give crudealdehyde 173B, which was used for the next step without purification.

To a solution of 173B and potassium carbonate (30 mmol) in MeOH (30 mL)was added dimethyl (diazomethyl)phosphonate (11 mmol). The reaction wasstirred at RT for 3 hr, and was then filtered through Celite. Thefiltrate was concentrated, and dissolved in 5% DCM/hexane, and thesolution was filtered through silica gel, rinsed with 10% DCM/hexanes.The filtrate was concentrated to give 173C.

173D was prepared by the same method as 003A, using 173C instead oftert-butylacetylene. MS calcd: (M+H)⁺=474. MS found: (M+H)⁺=474.

173 was then prepared by the same method as 129, using 173D instead of129C. MS calcd: (M+H)⁺=460. MS found: (M+H)⁺=460.

Example 1745-(1-Benzyl-cyclopropylethynyl)-3-[1-methyl-5-(4-methyl-cyclohexyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophene-2-carboxylicacid

174 was prepared by the same method as 172, using benzyl bromide insteadof dimethyl sulfate in the first step. MS calcd: (M+H)⁺=474. MS found:(M+H)⁺=474.

Example 1765-Cyclopentylethynyl-3-[1-methyl-4-(4-methyl-cyclohexyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-thiophene-2-carboxylicacid

176 was prepared by the same method as 031, using 111G instead of 014C.MS calcd: (M+H)⁺=412. MS found: (M+H)⁺=412.

Example 1775-(3-Methyl-hex-1-ynyl)-3-[1-methyl-4-(4-methyl-cyclohexyl)-1,2,5,6-tetrahydro-pyridin-3-yl]-thiophene-2-carboxylicacid

177 was prepared by the same method as 030, using 111G instead of 014C.MS calcd: (M+H)⁺=414. MS found: (M+H)⁺=414.

Example 1785-(3-methyl-4-(thiazole-4-carboxamido)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylicacid

178A was prepared by the same method as 002G, using triisopropyl borateinstead of iodine. MS calcd: (M+H)⁺=379. MS found: (M+H)⁺=379.

178B was prepared by the same method as 004A, using4-bromo-2-methylaniline and 178A instead of 002G and[4-({[(1,1-dimethylethyl)oxy]-carbonyl}amino)phenyl]boronic acid. MScalcd: (M+H)⁺=440. MS found: (M+H)⁺=440.

178C was prepared by the same method as 013A, using 178B instead of004B. MS calcd: (M+H)⁺=551. MS found: (M+H)⁺=551.

178 was then prepared by the same method as 129, using 178C instead of129C. MS calcd: (M+H)⁺=537. MS found: (M+H)⁺=537.

Example 1795-(3-methoxy-4-(thiazole-4-carboxamido)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylicacid

179A was prepared by the same method as 004A, using4-bromo-2-methoxylaniline and 178A instead of 002G and[4-({[(1,1-dimethylethyl)oxy]-carbonyl}amino)phenyl]boronic acid. MScalcd: (M+H)⁺=456. MS found: (M+H)⁺=456.

179B was prepared by the same method as 013A, using 179A instead of004B. MS calcd: (M+H)⁺=567. MS found: (M+H)⁺=567.

179 was prepared by the same method as 000, using 179B instead of 001J.MS calcd: (M+H)⁺=553. MS found: (M+H)⁺=553.

Example 1805-(3-cyano-4-(thiazole-4-carboxamido)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylicacid

180A was prepared by the same method as 004A, using2-amino-5-bromobenzonitrile and 178A instead of 002G and[4-({[(1,1-dimethylethyl)oxy]-carbonyl}amino)phenyl]boronic acid. MScalcd: (M+H)⁺=451. MS found: (M+H)⁺=451.

180B was prepared by the same method as 013A, using 180A instead of004B. MS calcd: (M+H)⁺=562. MS found: (M+H)⁺=562.

180 was prepared by the same method as 129, using 180B instead of 129C.MS calcd: (M+H)⁺=548. MS found: (M+H)⁺=548.

Example 1815-(3-ethyl-4-(thiazole-4-carboxamido)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylicacid

181A was prepared by the same method as 005B, using4-bromo-2-ethylaniline instead of 005A. MS calcd: (M+H)⁺=248. MS found:(M+H)⁺=248.

181B was prepared by the same method as 004A, using 181A instead of[4-({[(1,1-dimethylethyl)oxy]-carbonyl}amino)phenyl]boronic acid. MScalcd: (M+H)⁺=453. MS found: (M+H)⁺=453.

181C was prepared by the same method as 013A, using 181B instead of004B. MS calcd: (M+H)⁺=565. MS found: (M+H)⁺=565.

181 was prepared by the same method as 129, using 181C instead of 129C.MS calcd: (M+H)⁺=551. MS found: (M+H)⁺=551.

Example 1825-(3-chloro-4-(thiazole-4-carboxamido)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylicacid

182A was prepared by the same method as 062B, reacting4-bromo-2-chloroaniline with thiazole-4-carboxylic acid instead of4-iodobenzoic acid. MS calcd: (M+H)⁺=319. MS found: (M+H)⁺=319.

182B was prepared by the same method as 005B, using 182A instead of005A. MS calcd: (M+H)⁺=366. MS found: (M+H)⁺=366.

182 was prepared by the same method as 005, using 182B instead of 005B.MS calcd: (M+H)⁺=557. MS found: (M+H)⁺=557.

Example 1833-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-(4-(thiazole-4-carboxamido)-3-(trifluoromethyl)phenyl)thiophene-2-carboxylicacid

183A was prepared by the same method as 013A, using2-amino-5-bromobenzotriflouride instead of 004B. MS calcd: (M+H)⁺=352.MS found; (M+H)⁺=352.

183B was prepared by the same method as 005B, using 183A instead of005A. MS calcd: (M+H)⁺=399. MS found: (M+H)⁺=399.

183 was prepared by the same method as 005, using 183B instead of 005B.MS calcd: (M+H)⁺=591. MS found: (M+H)⁺=591.

Example 1845-(4-(5-methoxypyrazolo[1,5-a]pyrimidin-2-yl)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylicacid

A mixture of 3-(4-bromophenyl)-1H-pyrazol-5-amine (714 mg, 3.00 mmol),ethyl 3-ethoxyacrylate (649 mg, 4.50 mmol) and Cs₂CO₃ (1.47 g, 4.50mmol) in DMF (20 mL) was heated at 110° C. for 5 hr, cooled to RT, AcOH(10 mL) was added, stirred for 1 hr, sonicated in a mixture of H₂O andEtOAc, followed by filtration. The cake was washed with H₂O and dried invacuo overnight. The yellow solid 184A was dissolved in DMF (20 mL) andNaH (60% dispersion in mineral oil, 360 mg, 9.00 mmol) was added inportions. After stiffing at RT for 15 min, iodomethane (374 μL, 6.00mmol) was added and stirring continued for 5 hr. The reaction wasquenched with saturated NH₄Cl, extracted with EtOAc:MeOH (5:1, v/v), theorganic layer was washed with brine, dried over MgSO₄, concentrated andcolumn chromatography using 0-5% MeOH/DCM afforded 184B (minor product)and 185A (major product). MS calcd: (M+H)⁺=305. MS found: (M+H)⁺=305.

184C was prepared by the same method as 005B, using 184B instead of005A. MS calcd (M+H)⁺: 352. MS found (M+H)⁺: 352.

184 was prepared by the same method as 005, using 184C instead of 005B.MS calcd (M+H)⁺: 544. MS found (M+H)⁺: 544.

Example 1853-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-(4-(4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)phenyl)thiophene-2-carboxylicacid

185A was prepared along with 184B. MS calcd: (M+H)⁺=305. MS found:(M+H)⁺=305.

185B was prepared by the same method as 005B, using 185A instead of005A. MS calcd: (M+H)⁺=352. MS found: (M+H)⁺=352.

185 was prepared by the same method as 005, using 185B instead of 005B.MS calcd: (M+H)⁺=544. MS found: (M+H)⁺=544.

Example 1863-(1-((l-methyl-1H-pyrazol-4-yl)methyl)-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid

186 was prepared by the same method as 130, using1-methyl-1H-pyrazole-4-carbaldehyde instead of 88e. MS calcd:(M+H)⁺=602. MS found: (M+H)⁺=602.

Example 1875-(3-methyl-4-(pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylicacid

187 was prepared according to the following scheme:

A mixture of 4-bromo-2-methylbenzoic acid (2.15 g, 10 mmol), K₂CO₃ (4.14g, 30 mmol) and iodomethane (1.87 mL, 30 mmol) in ACN (50 mL) was heatedat 60° C. for 3 hr, concentrated, diluted in DCM and filtered throughsilica plug to afford 187A. Anhydrous ACN (2.05 mL, 39.3 mmol) was addeddropwise at −78° C. under N₂ to 2 M lithium diisopropylamide (LDA) inTHF/heptane/ethylbenzene (20 mL, 40 mmol) and the stirring at 78° C. for0.5 hr. A solution of 187A (3 g, 13.10 mmol) in dry THF (6 mL) was addeddropwise, stirred at 78° C. for 2.5 hr, quenched with sat. NH₄Cl,extracted with EtOAc:MeOH (5:1, v/v), the organic layer was washed withbrine, dried over MgSO₄, and concentrated to afforded 187B, which wasmixed together with hydrazine monohydrate and refluxed in EtOHovernight. The mixture was concentrated, followed by columnchromatography using 0-10% MeOH/DCM to afford 187C and 187D was preparedby the same method as 005A, using 187C instead of3-(4-bromophenyl)-1H-pyrazol-5-amine. MS calcd: (M+H)⁺: 289. MS found:(M+H)⁺=289.

187E was prepared by the same method as 005B, using 187D instead of005A. MS calcd: (M+H)⁺=336. MS found: (M+H)⁺=336.

187 was prepared by the same method as 005, using 187E instead of 005B.MS calcd: (M+H)⁺=528. MS found: (M+H)⁺=528.

Example 1883-(1-(2-hydroxyethyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid

Example 188 was prepared according to the following scheme:

To a solution of 111H (50 mg) in DCE (2 mL) were added(tert-butyldimethylsilyloxy)-acetaldehyde (100 mg), and sodiumtriacetoxyborohydride (100 mg). The reaction was stirred at RT for 15hr, and the mixture was filtered through Celite®, rinsed with EtOAc (20mL), and concentrated to give 188A.

To a mixture of 188A (0.1 mmol), and Pd(dppf)Cl₂ (0.003 mmol) under N₂was added DMF (2 mL), water (0.5 mL), Na₂CO₃ (0.3 mmol), and 159A (0.12mmol). The coupling reaction was run at 88° C. for 2 hrs. The solutionwas diluted with water (20 mL) and extracted (2×30 mL) with EtOAc. Theorganic phases were combined, washed with water (2×15 mL), dried(Na₂SO₄), evaporated, and purified by column chromatography (0-15%) MeOHin DCM to give 188B.

188B (30 mg) was dissolved in THF (2 mL), water (1 mL), and MeOH (1 mL).LiOH (2 M, 0.5 mL) was then added. The reaction was stirred at RT for 5hr, and then water (1 mL) and EtOAc (3 mL) were added. The organic layerwas separated, concentrated, and lyophilized to give 188. MS calcd:(M+H)⁺=552. MS found: (M+H)⁺=552.

Example 1893-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid

189 was prepared by the same method as 188, using(R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde instead of(tert-butyldimethylsilyloxy)-acetaldehyde. MS calcd: (M+H)⁺=622. MSfound: (M+H)⁺=622.

Example 1903-(1-(2,3-dihydroxypropyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid

190 was prepared by the hydrolysis of 189, using 6 M HCl and MeOH (1:3v:v) at RT for 2 hr. Upon completion, the mixture was extracted withEtOAc and washed with NaHCO₃, and brine. Concentration andlyophilization gave 190 as an off-white powder. MS calcd: (M+H)⁺=582. MSfound: (M+H)⁺=582.

Example 1913-(1-(2-hydroxyethyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)thiophene-2-carboxylicacid

188A (60 mg) was dissolved in THF (2 mL), water (1 mL), and MeOH (1 mL).LiOH (2 M, 0.5 mL) was then added. The reaction was stirred at RT for 5hr, and then water (1 mL) and EtOAc (3 mL) were added. The organic layerwas separated, and concentrated to give 191A.

To a mixture of 191A (0.1 mmol), and Pd(dppf)Cl₂ (0.003 mmol) under N₂were added DMF (2 mL), water (0.5 mL), Na₂CO₃ (0.3 mmol), and 005B (0.12mmol). The coupling reaction was run at 88° C. for 4 hr. The solutionwas diluted with water (20 mL) and extracted (2×30 mL) with EtOAc. Theorganic phases were combined, dried over Na₂SO₄, evaporated, andpurified by column chromatography (0-15%) MeOH in DCM to give 191. MScalcd: (M+H)⁺=543. MS found: (M+H)⁺=543.

Example 1923-(1-(2,3-dihydroxypropyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)thiophene-2-carboxylicacid

To a solution of 111H (60 mg) in DCE (2 mL) were added(R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde (100 mg), and sodiumtriacetoxyborohydride (100 mg). The reaction was stirred at RT for 15hr, and the mixture was filtered through Celite®, rinsed with EtOAc (20mL), and concentrated to give 189A.

189A (60 mg) was dissolved in THF (2 mL), water (1 mL), and MeOH (1 mL).LiOH (2 M, 0.5 mL) was then added. The reaction was stirred at RT for 5hr, and then water (1 mL) and EtOAc (3 mL) were added. The organic layerwas separated, concentrated, and lyophilized to give 192A.

To a mixture of 192A (0.1 mmol), and Pd(dppf)Cl₂ (0.003 mmol) under N₂were added DMF (2 mL), water (0.5 mL), Na₂CO₃ (0.3 mmol), and 005B (0.12mmol). The coupling reaction was run at 88° C. for 2 hrs. The solutionwas diluted with water (20 mL) and extracted (2×30 mL) with EtOAc. Theorganic phases were combined, washed with water (2×15 mL), dried(Na₂SO₄), evaporated, and purified by column chromatography (0-15%) MeOHin DCM to give 192B.

Hydrolysis of 192B was carried out by using 6 M HCl and MeOH (1:3 involume) at RT for 2 hr. The reaction mixture was extracted with EtOAcand washed with NaHCO₃, and brine. Concentration and lyophilization gave192 as an off-white powder. MS calcd: (M+H)⁺=573. MS found: (M+H)⁺=573.

Example 1933-(1-((l-methyl-1H-pyrazol-4-yl)methyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid

193 was prepared by the same method as 188, using1-methyl-1H-pyrazole-4-carbaldehyde instead of(tert-butyldimethylsilyloxy)-acetaldehyde. MS calcd: (M+H)⁺=602. MSfound: (M+H)⁺=602.

Example 1943-(1-((l-methyl-1H-pyrazol-4-yl)methyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)thiophene-2-carboxylicacid

194 was prepared by the same method as 191, using1-methyl-1H-pyrazole-4-carbaldehyde instead(tert-butyldimethylsilyloxy)-acetaldehyde. MS calcd: (M+H)⁺=593. MSfound: (M+H)⁺=593.

Example 1953-(1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid

195 was prepared by the same method as 188, using1,3-dimethyl-1H-pyrazole-4-carboxaldehyde instead of(tert-butyldimethylsilyloxy)-acetaldehyde at the first step. MS calcd:(M+H)⁺=616. MS found: (M+H)⁺=616.

Example 1963-(1-methyl-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(3-methyl-4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid

196 was prepared according to the scheme shown below.

Thiazole-4-carboxylic acid (1.42 g, 11 mmol) in DCM (20 mL) was treatedwith oxallyl chloride (8 mL, 2 M solution in DCM), followed by 2 dropsof DMF. After 1 hr at RT, solvent was evaporated, and the residue wasredissolved in DCM (20 mL). To the solution was added4-bromo-2-methylaniline (1.86 g, 10 mmol) and TEA (2 mL). After 30 minat RT, the reaction mixture was diluted with ether (100 mL), washed withwater, sodium bicarbonate, and brine. The organic layer was dried overanhydrous MgSO₄, filtered, concentrated and purified to give 196A.

A mixture of 196A (1 g), bis(pinacolato)diboron (1.5 g), AcOK (1.1 g)and Pd(dppf)Cl₂ (0.1 g) in dry 1,4-dioxane (20 mL) was heated to 100° C.under N₂ for 15 hr. The solvent was evaporated and the residuepartitioned between water (10 mL) and DCM (30 mL). The aqueous phase wasextracted further with DCM (20 mL) and the combined organic layers wereevaporated. The residue was purified by SPE chromatography, eluting withcyclohexane/EtOAc (3:1) to give 196B. MS calcd: (M+H)⁺=345. MS found:(M+H)⁺=345.

To a mixture of 111G (0.1 mmol), and Pd(dppf)Cl₂ (0.003 mmol) under N₂,were added DMF (2 mL), water (0.5 mL), Na₂CO₃ (0.3 mmol), and 196B (0.12mmol). The coupling reaction was run at 88° C. for 2 hr. The solutionwas diluted with water (20 mL) and extracted (2×30 mL) with EtOAc. Theorganic phases were combined, washed with water (2×15 mL), dried(Na₂SO₄), evaporated, and purified by column chromatography (0-15%) MeOHin DCM to give 196C.

196C (30 mg) was dissolved in THF (2 mL), water (1 mL), and MeOH (1 mL).LiOH (2 M, 0.5 mL) was then added. The reaction was stirred at RT for 5hr, and then water (1 mL) and EtOAc (3 mL) were added. The organic layerwas separated, concentrated, and lyophilized to give 196. MS calcd:(M+H)⁺=536. MS found: (M+H)⁺=536.

Example 1973-(1-(2-hydroxyethyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(3-methyl-4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid

197 was prepared by the same method as 196, using 188A instead of 111G.MS calcd: (M+H)⁺=566. MS found: (M+H)⁺=566.

Example 1985-(3-fluoro-4-(thiazole-4-carboxamido)phenyl)-3-(1-methyl-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)thiophene-2-carboxylicacid

198 was prepared by the same method as 059, using 111G instead of 002G.MS calcd: (M+H)⁺=540. MS found: (M+H)⁺=540.

Example 1993-(1-((l-methyl-1H-pyrazol-4-yl)methyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(3-methyl-4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid

199 was prepared by the same method as 188, using1-methyl-1H-pyrazole-4-carbaldehyde and 196B instead(tert-butyldimethylsilyloxy)-acetaldehyde. MS calcd: (M+H)⁺=616. MSfound: (M+H)⁺=616.

Example 2003-(4-(4,4-difluorocyclohexyl)-1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid

200 was prepared according to the following scheme:

To a stirred solution of 1,4-cyclohexanedione monoethylene acetal (2.7g, 17.8 mmol) and n-phenyltrifluoromethane-sulfonimide (7.6 g, 21.36mmol) in THF (77 mL) under N₂ at −78° C., was added 1 M sodiumbis-trimethylsilylamide in THF (20.0 mL, 19.6 mmol). The reaction wasstirred 8 hr, then quenched with H₂O, and extracted with ether. Thecombined ether extract layers were dried over MgSO₄, filtered andpurified by silica gel chromatography to give 200A as a colorless oil.

To a stirred solution of 200A (2.59 g, 9 mmol) in dioxane (38 mL) wasadded bis (pinacolato)diboron (2.74 g, 10.8 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl₂; 0.197 g, 0.27 mmol), 1,1′-bis(diphenylphosphino)ferrocene(0.150 g, 0.27 mmol), and AcOK (2.64 g, 27 mmol). The mixture wasdegassed by evacuating the reaction flask under vacuum followed by N₂back-fill (3×). Under N₂, the reaction was then heated to 90° C. andstirred overnight (approx. 16 hr). The reaction was cooled to RT anddiluted with H₂O. The mixture was extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and then purified by silica gel chromatography to give 200B asclear oil.

DMF (10 mL) and H₂O (2 mL) were added to a mixture of3-bromopyridine-4-boronic acid (0.3 g, 1.5 mmol), 200B (0.61 g, 1.77mmol), Pd(dppf)Cl₂ (0.065 g, 0.089 mmol), and Na₂CO₃ (0.563 g, 5.31mmol) under N₂ and stirred at 88° C. for 3 hr. The reaction was cooledto RT, and to it was added ice-water and EtOAc. The layers wereseparated and the aqueous layer was back-extracted with EtOAc (2×). Thecombined organic layers were then washed with brine, dried overanhydrous Na₂SO₄, filtered over Celite®, and concentrated under reducedpressure. The product was purified by flash chromatography (silica gel)eluting with 0-5% methanol (MeOH) in CH₂Cl₂ to give 200C as an off-whitesolid.

To a stirred solution of 002A (2.41 g, 9 mmol) in dioxane (38 mL) wasadded bis (pinacolato)diboron (2.74 g, 10.8 mmol), Pd(dppf)Cl₂ (0.197 g,0.27 mmol), dppf (0.150 g, 0.27 mmol), and AcOK (2.64 g, 27 mmol). Themixture was degassed by evacuating the reaction flask under vacuumfollowed by N₂ back-fill (3×). Under N₂, the reaction was then heated to90° C. and stirred overnight (approx. 16 hr). The reaction was cooled toRT and diluted with H₂O. The mixture was extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and then purified by silica gel chromatography to give 200D asa solid.

DMF (10 mL) and H₂O (2 mL) were added to a mixture of 200C (0.41 g, 1.4mmol), 200D (0.20 g, 1 mmol), Pd(dppf)Cl₂ (0.033 g, 0.0455 mmol), andNa₂CO₃ (0.3 g, 2.8 mmol) under N₂ and stirred at 88° C. for 3 hr. Thereaction was cooled to RT, and to it was added ice-water and EtOAc. Thelayers were separated and the aqueous layer was back-extracted withEtOAc (2×). The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄, filtered over Celite®, and concentrated underreduced pressure. The residue was purified by flash chromatography(silica gel) eluting with 0-5% MeOH in CH₂Cl₂ to give 200E as a solid.

200E (110 mg, 0.31 mmol) was dissolved in MeOH (15 mL), and 10% Pd/C (20mg) was added as the catalyst. Hydrogenation under 50 psi H₂ was runovernight. Filtration and concentration gave 200F.

A solution of 200F (100 mg, 0.3 mmol, 1.0 equiv.) was treated with 6MHCl in MeOH at 60.deg. C and then concentrated to dryness. The crude oilwas again dissolved in CH₂Cl₂ (5 mL) and was treated at 0° C. with DAST(1.2 mmol). After being stirred at 0° C. for 30 min and at 25° C. for 48hr, the reaction mixture was diluted (CH₂Cl₂), washed (lx saturatedaqueous NaHCO₃, and 1× brine), dried (Na₂SO₄), and concentrated underreduced pressure. Flash chromatography of the residue (SiO₂, 10 percentEtOAc/Hexanes) provided 200G as a yellow solid.

Methyl iodide (0.08 mL, 1.278 mmol) was added to a solution of 200G (60mg, 0.17 mmol) in ACN (5 mL) and the mixture was stirred for 3 hr at 80°C. The reaction mixture was cooled to RT and concentrated in vacuo. Thecrude intermediate 200G1 was used directly in the next step.

Sodium borohydride (42 mg, 1.1 mmol) was added to a solution of 200G1(60 mg, 0.175 mmol) in MeOH (6 mL) at RT with constant stirring. Thereaction mixture was stirred overnight at 80° C. The reaction mixturewas quenched with water (20 mL) and extracted with EtOAc (3×20 mL). Theorganic layers were combined, dried over anhydrous Na₂SO₄, andconcentrated to obtain 200H as yellow oil.

A solution of 200H (50 mg, 0.14 mmol) in dry THF (4 mL) was added at−77° C. under N₂ to 2 M lithium diisopropylamide (LDA) inTHF/heptane/ethylbenzene (0.01 mL) maintaining an internal temperature<−70° C. The stirring was continued at −77° C. for 2.5 hr. A solution ofiodine (23 mg) was added to the stirred reaction mixture maintaining aninternal temperature <−70° C. After stirring under N₂ at −77° C. for 1.5hr, the reaction mixture was quenched by addition of saturated NH₄Clsolution and warmed to 0° C. The mixture was diluted with 5% sodiumthiosulfate solution, then the organic phase was separated and theaqueous phase was extracted with EtOAc. The combined organic phases weredried (Na₂SO₄), filtered, and evaporated. The product was dried to give2001.

To a mixture of 2001 (0.1 mmol), and Pd(dppf)Cl₂ (0.003 mmol) under N₂were added DMF (2 mL), water (0.5 mL), Na₂CO₃ (0.3 mmol), and 159A (0.12mmol). The coupling reaction was run at 88° C. for 2 hrs. The solutionwas diluted with water (2 mL) and extracted (2×3 mL) with EtOAc. Theorganic phases were combined, washed with water (2×1.5 mL), dried(Na₂SO₄), evaporated, and purified by column chromatography (0-5%) MeOHin DCM to give 200J.

200J (20 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated in hexane and washedmore with hexane. The powder of 200 was obtained after lyophilization.MS calcd: (M+H)⁺=544. MS found: (M+H)⁺=544.

Example 2013-(5-(2,4-dichlorophenyl)-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid

201 was prepared according to the following scheme.

DMF (10 mL) and H₂O (2 mL) were added to a mixture of2,4-dichlorophenylboronic acid (0.26 g, 1.4 mmol), 002B (0.27 g, 0.91mmol), Pd(dppf)Cl₂ (0.033 g, 0.0455 mmol), and Na₂CO₃ (0.3 g, 2.8 mmol)under N₂, and the mixture was stirred at 92° C. for 4 hr. The reactionwas cooled to RT, and to it was added ice-water and EtOAc. The organiclayer was washed with water (3×) and the combined aqueous layers wereback-extracted with EtOAc (2×). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. The product was purified by flash chromatography (silica gel),eluting with 0-5% MeOH in CH₂Cl₂ to give 201A as a solid. MS calcd:(M+H)⁺=365. MS found: (M+H)⁺=365.

Methyl iodide (0.04 mL, 1.278 mmol) was added to a solution of (93 mg,0.256 mmol) of 201A in 5 mL of ACN, and the mixture was stirred for 3 hrat 80° C. The reaction mixture was cooled to RT and concentrated invacuo. The crude 201B was used directly in the next step.

Sodium borohydride (42 mg, 1.1 mmol) was added to a solution of 201B(110 mg, 0.275 mmol) in MeOH (6 mL) at RT with constant stiffing. Thereaction mixture was stirred overnight at 80° C. The reaction mixturewas quenched with water (20 mL) and extracted with EtOAc (3×20 mL). Theorganic layers were combined, dried over anhydrous Na₂SO₄, andconcentrated to obtain the compound as brown oil, which was purified bycolumn chromatography (silica gel, 0-10% MeOH in CH₂Cl₂) to yield 201C.

A solution of 201C (1 g, 3 mmol) in dry THF (10 mL) was added dropwiseat −77° C. under N₂ to 2 M lithium diisopropylamide (LDA) inTHF/heptane/ethylbenzene (3 mL) maintaining an internal temperature<−70° C. The stiffing was continued at −77° C. for 2.5 hr. A solution ofiodine (2.3 g) in dry THF (5 mL) was added dropwise to the stirredreaction mixture maintaining an internal temperature <−70° C. Afterstirring under N₂ at −77° C. for 1.5 hr, the reaction mixture wasquenched by addition of saturated NH₄Cl solution and warmed to 0° C. Themixture was diluted with 5% sodium thiosulfate solution, then theorganic phase was separated and the aqueous phase was extracted withEtOAc. The combined organic phases were dried (Na₂SO₄), filtered, andevaporated. The product was dried to give 201D.

To a mixture of 201D (0.1 mmol), and Pd(dppf)Cl₂ (0.003 mmol) under N₂were added DMF (2 mL), water (0.5 mL), Na₂CO₃ (0.3 mmol), and 159A (0.12mmol). The coupling reaction was run at 88° C. for 2 hrs. The solutionwas diluted with water (20 mL) and extracted (2×30 mL) with EtOAc. Theorganic phases were combined, washed with water (2×15 mL), dried(Na₂SO₄), evaporated, and purified by column chromatography (0-15%) MeOHin DCM to give 201E.

201E (30 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated in hexane and washedmore with hexane. The powder of 201 was obtained after lyophilization.MS calcd: (M+H)⁺=571. MS found: (M+H)⁺=571.

Example 2023-(1-methyl-5-(p-tolyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid

202 was prepared by the same method as 201, using p-tolylboronic acidinstead of 2,4-dichlorophenylboronic acid. MS calcd: (M+H)⁺=516. MSfound: (M+H)⁺=516.

Example 2035-(6-aminopyridin-3-yl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylicacid

DMF (10 mL) and water (2 mL) were added to a mixture of4-carboxyphenylboronic acid (0.23 g, 1.4 mmol), 002G (0.43 g, 0.9 mmol),Pd(dppf)Cl₂ (0.033 g, 0.0455 mmol), and Na₂CO₃ (0.3 g, 2.8 mmol) underN₂, and stirred at 92° C. for 4 hr. The reaction was cooled to RT, andto it was added ice-water and EtOAc. The organic layer was washed withwater (3×) and the combined aqueous layers were back-extracted withEtOAc (2×). The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄, and concentrated under reduced pressure. Theproduct was purified by flash chromatography (silica gel), eluting with0-5% MeOH in CH₂Cl₂ to give 203A. MS calcd: (M+H)⁺=468. MS found:(M+H)⁺=468.

203A (25 mg) was dissolved in THF (2 mL) and EtOH (1 mL). LiOH (2 M, 0.5mL) was then added. The reaction was stirred at RT for 16 hr, and thendiluted with EtOAc. The organic layer was washed with water andconcentrated. The final product was precipitated out in hexane andwashed more with hexane. The powder of 203 was obtained withlyophilization. MS calcd: (M+H)⁺=412. MS found: (M+H)⁺=412.

Example 2043-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-(6-(thiazole-4-carboxamido)pyridin-3-yl)thiophene-2-carboxylicacid

1,3-Thiazole-4-carboxylic acid (20 mg) was dissolved in DMF (3 mL). HATU(65 mg) and DIPEA (0.06 mL) were added and the reaction mixture wasstirred at RT for 15 min. 203 (41 mg, 0.1 mmol) was added and thereaction mixture was stirred at RT for 1 hr. The mixture was evaporatedin vacuo and the residue was dissolved in DCM. The resulting mixture waswashed with saturated NaHCO₃ solution (2×) followed by 2 N HCl (2×). TheDCM was separated and concentrated to obtain the compound as a brownoil, which was purified by column chromatography to give 204. MS calcd:(M+H)⁺=523. MS found: (M+H)⁺=523.

Example 2053-(5-Cyclohexyl-1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid

205 was prepared according to the following scheme:

p-Tolylsulfonylhydrazine (15.2 g, 81.5 mmol) was added to absolute EtOH(25 mL) in a 250 mL flask equipped with a magnetic stir bar.Cyclohexanone (8 g, 81.5 mmol) was added to the suspension, and then thereaction mixture was heated to 100° C. After several minutes, a whiteprecipitate was formed. Then the reaction mixture was cooled using anice-water bath to precipitate most of hydrazine, which was collected byfiltration, and washed thoroughly with ice-cold EtOH. Air drying underreduced pressure for 2 hr afforded 205A (15 g, 69%) as a white solid.

To a flame-dried 500-mL round-bottom flask equipped with a magnetic stirbar and rubber septum, 205A (6 g, 22.5 mmol) was added followed by 80 mLof anhydrous hexane. To this mixture was added anhydroustetramethylethylenediamine (TMEDA; 67.5 mL). The reaction mixture wascooled to −78° C. and maintained at this temperature for 15 min, afterwhich 36 mL (90 mmol) of 2.5 M n-BuLi was added dropwise over 30 min.The reaction mixture was stirred for 1 hr at −78° C., then warmed to RTand stirred for 1.5 hr. The reaction mixture was then re-cooled to −78°C. and maintained for another 15 min, after which 16.7 g (90 mmol) of2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane was added. Thereaction mixture was stirred for another hour at −78° C., then warmed toRT and stirred for 3 hr. The reaction was quenched with sat. NH₄Cl andextracted with ether (3×). The combined organic extracts were dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by column chromatography (hexane) to afford 8 (2.8 g, 60%) as alight yellow oil.

A mixture of 002B (0.5 g, 1.68 mmol), 205B (0.538 g, 2.52 mmol) andNa₂CO₃ (0.533 g, 5.04 mmol) in DMF/H₂O (5 mL/1 mL) was degassed andplaced under argon atmosphere (Ar). Pd(dppf)Cl₂ (61 mg, 168 μmol) wasadded under Ar. The mixture was stirred at 80° C. for 3 hr. The reactionmixture was cooled to RT, diluted in EtOAc and washed with H₂O. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated to give the crude product which was purifiedby column chromatography to give 205C (0.36 g, 68%) as a yellow solid.

A mixture of 205C (250 mg, 83.6 mmol) and 10% Pd/C (wet, 330 mg) in MeOH(8 mL) was stirred for 6 days at RT under H₂ (0.5 MPa). When thereaction finished, the mixture was filtered to remove the catalyst andthe filtrate was concentrated to give 205D (200 mg, 79%) as a yellowoil.

A mixture of 205D (125 mg, 0.417 mmol) and CH₃I (0.592 mg, 4.17 mmol) inACN (15 mL) was refluxed at 80° C. The resultant reaction mixture wasconcentrated in vacuo to give the quaternary ammonium salt, which wasthen dissolved in MeOH (15 mL). The resulting solution was cooled to 0°C., and NaBH₄ (158 mg, 4.17 mmol) was added. Then the reaction mixturewas allowed to warm to RT and heated to 80° C. for 6 hr. When TLCanalysis indicated no further consumption of the quaternary ammoniumsalt, the solvent was removed and the residue was purified by columnchromatography to give 205E (94 mg, 71%) as a yellow oil.

n-BuLi (187 μL, 469.54 μmol) was added dropwise to diisopropylamine(54.8 μL, 391.28 μmol) in THF (6 mL) at −20° C. under Ar, and themixture was stirred for 1 hr at −20° C. 205E (50 mg, 156.51 μmol) in THF(10 mL) was added to the lithium diisopropylamide (LDA) mixture at −78°C. and stirred for 2.5 hr. I₂ (119.17 mg, 469.54 μmol) in THF (10 mL)was added to the solution and stirred for 1.5 hr at −78° C., thenallowed to warm to RT and stirred overnight. The reaction mixture wasquenched with sat. NH₄Cl, diluted in 5% Na₂S₂O₃, extracted with EtOAc,washed with brine, dried over Na₂SO₄, and concentrated to afford thecrude product 205F (71 mg), which was used without further purification.

A mixture of 205F (50 mg, 112 μmol), (4-aminophenyl) boronic acidhydrochloride (29.06 mg, 168 μmol) and K₃PO₄ (71.5 mg, 336.81 μmol) inDMF/H₂O (1 mL/0.2 mL) was degassed and placed under Ar. Pd(dppf)Cl₂ (4.1mg, 5.6 μmol) was added under Ar. The mixture was stirred at 88° C. for4 hr. The reaction mixture was cooled to RT, diluted in EtOAc and washedwith H₂O. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated to give the crude product, which waspurified by prep-TLC to give 205G (40 mg, 86.9%) as a brown oil.

A mixture of 205G (40 mg, 97.43 μmol), thiazole-4-carboxylic acid (18.87mg, 146.14 μmol), EDCI (28 mg, 146.14 μmol) and hydroxybenzotriazole(HOBT; 19.75 mg, 146.14 μmol) in DCM (5 mL) was stirred at RT overnight.The reaction mixture was diluted in DCM and washed with H₂O. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated to give the crude product which was purifiedby prep-TLC to give 205H (12 mg, 23.6%) as a yellow solid.

A mixture of 205H (12 mg, 23 μmol), LiOH (1 N, 100 μL), MeOH (0.6 mL),H₂O (0.1 mL) and THF (0.3 mL) was stirred for 3 days at RT. The reactionmixture was concentrated, and then diluted in 5 mL H₂O and extractedwith ether. Then aqueous phase was acidified by the addition of 1 N HClto pH 3-4, then extracted with EtOAc, washed with brine, dried overNa₂SO₄ and concentrated to give the title compound (6.8 mg, 58.1%) as ayellow oil. MS calcd: (M+H)⁺=508.7. MS found: (M+H)⁺=508.7.

Example 2063-(5-Cycloheptyl-1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-phenyl-thiophene-2-carboxylicacid

206 was prepared according to the following scheme.

206A was prepared by the same method as 205B, using cycloheptanoneinstead of cyclohexanone.

A mixture of 001F (40 mg, 107.2 μmol), 206 A (119.1 mg, 536.2 μmol) andNa₂CO₃ (34.1 mg, 321.6 μmol) in DMF/H₂O (2 mL/0.6 mL) was degassed andplaced under Ar atmosphere. Pd(dppf)Cl₂ (3.9 mg, 5.36 μmol) was addedunder Ar atmosphere. The mixture was stirred for 3 hr at 80° C. Thereaction mixture was cooled to RT, diluted in EtOAc and washed with H₂O.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated to give the crude product which was purifiedby column chromatography to give 206B (36.9 mg, 88.5%) as a yellowsolid.

A mixture of 206B (36.9 mg, 94.8 μmol) and 10% Pd/C (wet, 107 mg) inMeOH (2 mL) was stirred for 6 days at RT under H₂ (0.5 MPa). When thereaction finished, the mixture was filtered to remove the catalyst, andthe filtrate was concentrated to give 206C (18.2 mg, 49%).

A mixture of 206C (18.2 mg, 46.5 μmol) and CH₃I (26.4 mg, 186.1 μmol) inACN (2 mL) was refluxed at 80° C. When TLC analysis indicated totalconsumption of the starting material, the solvent and the remaining CH₃Iwhich were removed in vacuo to give quaternary ammonium salt. Thequaternary ammonium salt was dissolved by MeOH (2 mL). The resultingsolution was cooled to 0° C. and NaBH₄ (17.6 mg, 465 μmol) was added tothe solution. Then the reaction mixture was brought to RT and heated to80° C. for 6 hr. When TLC analysis indicated no further consumption ofthe salt, the solvent was removed and the residue was purified by columnchromatography to give 206D (18 mg, 95%) as a yellow oil.

A mixture of 206D (18 mg, 43.9 μmol), LiOH (2 N, 100 μL), MeOH (0.6 mL),H₂O (0.1 mL) and THF (0.3 mL) was stirred for 4 days at RT. The reactionmixture was concentrated, and then diluted in 5 mL H₂O and extractedwith ether. Then aqueous phase was acidified by adding 1 N HCl to pH3-4, then extracted with EtOAc, washed with brine, dried over Na₂SO₄ andconcentrated to give 206 (17 mg, 88.5%) as a yellow solid. MS calcd:(M+H)⁺=396.6. MS found: (M+H)⁺=396.6.

Example 2073-(5-Cyclopentyl-1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-phenyl-thiophene-2-carboxylicacid

207 was prepared by the same method as 206, using cyclopentanone insteadof cycloheptanone. MS calcd: (M+H)⁺=368.5. MS found: (M+H)⁺=368.5.

Example 2083-[5-(4-Chloro-phenyl)-1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl]-5-phenyl-thiophene-2-carboxylicacid

208 was prepared according to the following scheme.

A mixture of 001F (30 mg, 80.16 μmol), (4-chloro-phenyl)boronic acid(18.8 mg, 120.24 μmol), and Na₂CO₃ (22.6 mg, 240.48 μmol), in DMF/H₂O(1.5 mL/0.4 mL) was degassed and placed under Ar. Pd(dppf)Cl₂ (5.8 mg,8.016 μmol) was added under Ar. The mixture was stirred at 80° C. for 3hr. The mixture was cooled to RT, diluted in EtOAc and washed with H₂O.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated to give the crude product, which was purifiedby column chromatography to give 208A (32.5 mg, 100%) as a solid.

A mixture of 208A (32.5 mg, 80 μmol) and CH₃I (113.5 mg, 800 μmol) inACN (5 mL) was refluxed at 80° C. When TLC analysis indicated no furtherconsumption of the starting material, solvent and remaining CH₃I wereremoved in vacuo to give the quaternary ammonium salt. The salt wasdissolved by MeOH (5 mL). The resulting solution was cooled to 0° C. andNaBH₄ (30.74 mg, 800 μmol) was added. Then the mixture was allowed towarm to RT and then heated at 80° C. for 6 hr. When TLC analysisindicated no further consumption of the quaternary ammonium salt, thesolvent was removed and the residue was purified by columnchromatography to give 208B (37 mg).

A mixture of 208B (37 mg, 87.4 μmol), LiOH (2 N, 300 μL), MeOH (0.6 mL),H₂O (0.1 mL) and THF (0.3 mL) was stirred for 4 days at RT. The reactionmixture was concentrated, and then diluted in 5 mL H₂O and extractedwith ether. Then aqueous phase was acidified by adding 1 N HCl to pH3-4, then extracted with EtOAc, washed with brine, dried over Na₂SO₄,and concentrated to give 208 (17 mg, 51.7%) as a solid. MS calcd:(M+H)⁺=410.9. MS found: (M+H)⁺=410.9.

Example 2093-(1-Methyl-5-pentyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-phenyl-thiophene-2-carboxylicacid

209 was prepared according to the following scheme.

A mixture of 001F (30 mg, 80.4 μmol), pent-1-yne (27.3 mg, 402 μmol),K₂CO₃ (33.3 mg, 241.2 μmol), Pd(OAc)₂ (1.8 mg, 24.1 μmol) and PPh₃ (2.1mg, 24.1 μmol) in THF (2 mL) was degassed and placed under Ar. Themixture was stirred at 70° C. overnight. The reaction mixture was cooledto RT, concentrated in vacuo, diluted in EtOAc, and washed with H₂O. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated to give the crude product, which was purifiedby prep-TLC to give 209A (18 mg, 62%) as a light yellow solid.

A mixture of 209A (18 mg, 94.8 μmol) and 10% Pd/C (dry, 18 mg) in MeOH(2 mL) was stirred at RT under H₂ (0.5 MPa) for 2 days. When thereaction finished, the mixture was filtered to remove the catalyst, andthe filtrate was concentrated to give 209B (12 mg, 60%).

A mixture of 209B (12 mg, 32.9 μmol) and CH₃I (46.6 mg, 329 μmol) in ACN(2 mL) was refluxed at 60° C. When TLC analysis indicated no furtherconsumption of the starting material, the solvent and CH₃I which had notbeen consumed were removed in vacuo to give quaternary ammonium salt.The salt was dissolved in MeOH (2 mL), and the resulting solution wascooled to 0° C., and NaBH₄ (12.4 mg, 329 μmol) was added. Then themixture was allowed to rise to RT and was then heated at 80° C. for 6hr. When TLC analysis indicated no further consumption of the salt, thesolvent was removed and the residue was purified by prep-TLC to give209C (9.8 mg, 78%) as an oil.

A mixture of 209C (9.8 mg, 25.6 μmol), LiOH (2 N, 80 μL), MeOH (0.6 mL),H₂O (0.1 mL) and THF (0.3 mL) was stirred for 5 days at RT. The reactionmixture was concentrated, and then diluted in 3 mL H₂O and extractedwith ether. The aqueous phase was acidified by adding 1 N HCl to pH 3-4,then extracted with EtOAc, washed with brine, dried over Na₂SO₄ andconcentrated to give 209 (7.5 mg, 79.8%) as a light brown oil. MS calcd:(M+H)⁺=370.5. MS found: (M+H)⁺=370.5.

Example 2103-(4-Cyclohexyl-1-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl}-thiophene-2-carboxylicacid

210 was prepared according to the following scheme.

n-BuLi (2.5 M, 45.9 mL, 114.7 mmol) was added to diisopropylamine (16mL, 114.7 μmol) in anhydrous ether (80 mL) at −20° C. under Aratmosphere, the mixture was stirred at −20° C. for 1.5 hr.3-Bromo-pyridine (15 g, 95.6 mmol) in anhydrous ether (30 mL) was addeddrop wise to the mixture at −78° C. and stirred for another 1.5 hr,after which cyclohexanone (12.9 g, 114.7 mmol) in anhydrous ether (30mL) was added, and the solution was stirred for 1 hr at −78° C., andthen allowed to warm to RT. The reaction mixture was quenched with sat.NH₄Cl, diluted in EtOAc, washed with water and brine, dried over Na₂SO₄,concentrated and purified to afford 3 (3.68 g, 15.3%) as a white solid.

A mixture of 210A (3.68 g, 14.4 mmol) in HBr (40%, 45 mL) was refluxedat 100° C. overnight. The pH was adjusted to around 9 by progressivelyadding solid Na₂CO₃ in ice-bath, extracted with EtOAc, concentrated andpurified by column chromatography to afford 210B (2.6 g, 76.5%) as ayellow solid.

n-BuLi (2.5 M, 6.3 mL, 15.8 mmol) was added dropwise to 210B (2.5 g,10.5 mmol) in THF (20 mL) at −78° C. under Ar, and then the mixture wasstirred at −78° C. for 1 hr. Triisopropyl borate (3.7 mL, 15.8 mmol) inTHF (10 mL) was added dropwise to the mixture at −78° C. and thereaction mixture was stirred for 2 hr and then allowed to warm to RT andstirred overnight. The reaction mixture was quenched with sat. NaH₂PO₄and stirred 30 min, extracted using EtOAc, washed with brine, dried overNa₂SO₄, concentrated to afford 210C (3 g) as a light brown oil. Crudeproduct was used for next step directly.

A mixture of 210C (3 g, 14.8 mmol), 002A (3.95 g, 14.8 mmol) and Na₂CO₃(4.7 g, 44.4 mmol) in DMF/H₂O (25 mL/5 mL) was degassed and placed underAr atmosphere. Pd(dppf)Cl₂ (541 mg, 740 μmol) was added under Ar. Themixture was stirred at 80° C. for 3 hr. The reaction mixture was cooledto RT, diluted in EtOAc and washed with H₂O. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated togive the crude product which was purified by column chromatography togive 210D (2.15 g, 48.5%) as a brown solid.

210 was then prepared using the same method as 205, using 210D insteadof 205C. MS calcd: (M+H)⁺=508.7. MS found: (M+H)⁺=508.7.

Example 2113-(5-Cyclohexyl-1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid

211 was prepared by the following scheme:

A mixture of 205F (40 mg, 90 μmol), 3,3-dimethyl-but-1-yne (73.8 mg, 900₁J MOO, K₂CO₃ (37.2 mg, 270 μmol), Pd(OAc)₂ (2.4 mg, 9 μmol) and PPh₃ (2mg, 9 μmol) in THF (2 mL) was degassed and placed under Ar atmosphere.The mixture was stirred at 70° C. overnight. The reaction mixture wascooled to RT, removed solution, diluted in EtOAc, and washed with H₂O.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated to give the crude product which was purifiedby prep-TLC to give 211A (11.2 mg, 31%) as an oil.

A mixture of 211A (11.2 mg, 28 μmol), LiOH (2 N, 80 μL), MeOH (0.6 mL),H₂O (0.1 mL) and THF (0.3 mL) was stirred for 5 days at RT. The reactionmixture was concentrated, and then diluted in 6 mL H₂O and extractedwith ether. Then aqueous phase was acidified by adding 1 N HCl to pH3-4, then extracted with EtOAc, washed with brine, dried over Na₂SO₄ andconcentrated to give 1976 (8.7 mg, 80.5%) as a light brown oil. MScalcd: (M+H)⁺=386.6. MS found: (M+H)⁺=386.6.

Example 212 RNA-Dependent RNA HCV NS5B (Polymerase) Assay and IC₅₀Determination

In vitro RNA-dependent RNA polymerase activity was determined in areaction mixture (50 μL) containing 50 mM Tris-HCl, pH 7.5, 5 mM MgCl₂,1 mM dithiothreitol, 0.5% Triton® X-100, 10 μM of UTP, 0.1-0.5 μCi ofα-³²P UTP (Perkin Elmer Life Sciences), 1 μg of polyA:U16 (MidlandOligo), and 0.6 μg of purified HCV1b NS5B polymerase delta 21. Differentconcentrations of compounds were added to the reaction mixtures. Thereaction was carried out at RT (23° C.) for 60 min and then stopped bythe addition of 100 μL of 50 mM EDTA. The reaction mixtures werefiltered through either a DE81 membrane or a positively charged nylonmembrane, and the membranes were then extensively washed with 30 mMsodium citrate, pH 7.0 and 300 mM NaCl. The radiolabeled RNA productswere quantitated using a Storm™ Phosphorlmager™ (GE Life Sciences). IC₅₀values were calculated using GraFit 6 and GraphPad Prism 5 fromtriplicate assays. Data (IC₅₀) obtained for compounds of the inventionare summarized in Tables 1 and 2.

Example 213 HCV Replicon Assay and EC₅₀ Determination

The antiviral activity of compounds against hepatitis C virus wasdetermined by a hepatitis C virus replicon reporter cell line developedby Bartenschlager (Lohmann et al., Science 1999, 285:110-113;Bartenschlager et al., Antiviral Res 2003, 60:91-102). This cell-basedassay utilized a liver cell carcinoma (Huh-7) cell line stablytransformed with an HCV1b replicon containing a luciferase reportergene. Varied concentrations of compounds were added to the reporter cellline, and further incubated at 37° C. for 72 hr in DMEM supplementedwith 10% FCS. The inhibitory effects of experimental compounds or thereference compound, interferon alpha (INFα), on HCV replication weremeasured by luciferase activity using the Britelite™ plus luminescencereporter gene kit (Perkin Elmer, Shelton, Conn.). The Britelite plusreagent was added to the 96-well plates containing the HCV reportercells, and luminescence was measured within 15 min using a Wallac 1450Microbeta® Trilux liquid scintillation counter. EC₅₀ values werecalculated using GraFit 6 and GraphPad Prism 5 from triplicate HCVreplicon assays. Data (EC₅₀) obtained for compounds of the invention aresummarized in Tables 1 and 2.

In Table 1, representative IC₅₀ data obtained using the biochemicalassay of Example 212 and representative EC₅₀ data obtained using thecellular assay of Example 213 are presented as follows: +++<3 μM; 3μM<++<10 μM; +>10 μM; and ND=no data.

TABLE 1 Compound IC₅₀ EC₅₀ Compound IC₅₀ EC₅₀ 178 ND +++ 199 +++ ND 179+++ ND 200 +++ ++ 180 ND +++ 201 ND +++ 181 +++ ND 202 ND +++ 183 ND +++203 +++ ND 184 +++ ND 204 ND +++ 185 ND +++ 206 +++ ND 187 +++ ND 208 +ND 196 ND +++ 209 ++ ND 197 ND +++

TABLE 2 Compound IC₅₀ EC₅₀ Compound IC₅₀ EC₅₀ 182 +++ ND 194 ND +++ 186+++ ND 195 ND +++ 188 ND +++ 198 +++ ND 189 +++ ND 205 ND +++ 190 ++++++ 207 ++ ND 191 ND +++ 210 +++ ND 192 ND +++ 211 +++ ND 193 ND +++

All publications, including but not limited to patents and patentapplications, cited in this specification are incorporated by referenceherein for all that they disclose, as if each individual publicationwere specifically and individually set forth in its entirety.

While a number of aspects and embodiments of this invention have beendescribed, it is apparent that the basic examples and general formulasand schemata may be altered to provide other embodiments that utilizethe compounds and methods of this invention. Therefore, it will beappreciated that the scope of this invention is to be defined by theappended claims rather than by the specific embodiments that have beenrepresented by way of example.

What is claimed is:
 1. A compound according to Formula I:

or a pharmaceutically acceptable salt thereof, wherein: X is —NR¹— and Yis —CH₂—; R¹ is —C₅₋₆hydroxyalkyl, —S(O)₂—C₀₋₄alkyl-R^(O),—C₀₋₄alkyl-R^(O), —C₀₋₃alkyl-C(O)—C₀₋₄alkyl-R^(O), or—C₀₋₃alkyl-C(O)O—C₀₋₄alkyl-R^(O); wherein: R^(M) and R^(N) areindependently hydrogen or —C₁₋₄alkyl; and R^(O) is (a) a 5- to7-membered cycloalkyl group, substituted with a —C₁₋₃alkyl, aryl,—O-aryl, or —NR^(M)R^(N) moiety, (b) a 7-membered cycloalkyl group[optionally substituted with a hydroxyl], or (c) a 6- to 10-memberedmonocyclic or bicyclic aryl, substituted with one to three moietiesindependently selected from —C₁₋₄alkyl, halogen, —NR^(M)R^(N),—C₁₋₄haloalkyl, —C₁₋₄alkoxy, —C₁₋₄hydroxyalkyl, cyano, —O-aryl, andaryl, provided that at least one such substitution is —C₁₋₄alkoxy,—C₁₋₄hydroxyalkyl, cyano, or —O-aryl; R² is —C₁₋₅alkyl optionallysubstituted with 1-5 halogens, —C₁₋₅alkoxy, —C₅₋₇cycloalkyl-C₀₋₃alkyl inwhich the alkyl is optionally substituted with 1-3 halogens,—C₁₋₄alkyl-C₃₋₅cycloalkyl, or phenyl optionally substituted with 1 or 2halogens or —C₁₋₃alkyl groups optionally substituted with 1-3 halogens;R³ is —R^(A)—R^(B); wherein R^(A) is a phenyl moiety optionallysubstituted with one or two Z, in which each Z is independently halogen,—C₁₋₃alkyl, —C₁₋₃haloalkyl, —C₁₋₃alkoxy, or cyano; and wherein R^(B) is—N(R^(U))C(O)—R^(Q); wherein R^(Q) is thiazolyl, optionally substitutedwith one or two R^(Z), in which each R^(Z) is independently —C₁₋₃alkyl,—C₁₋₃alkoxy, or —NR^(M)R^(N); and R^(U) is hydrogen or —C₁₋₄alkyl;provided that, when R^(A) is phenyl, then R^(B) appears at the para ormeta position relative to the thiophene moiety; and R⁴ is hydrogen,—C₁₋₄alkyl, —C₁₋₄alkyl-OC(O)O—C₁₋₄alkyl, —C₁₋₄alkyl-OC(O)—C₁₋₄alkyl,—C₁₋₄alkyl-OC(O)O—C₃₋₆cycloalkyl, —C₀₋₃alkyl-C₅₋₆aryl, or—C₁₋₄alkyl-NR^(V)R^(W); and R^(V) and R^(W) are independently hydrogenor —C₁₋₄alkyl.
 2. A compound according to claim 1, wherein R^(A) isphenyl.
 3. A compound according to claim 2, wherein R^(B) appears at thepara position relative to the thiophene moiety.
 4. A compound accordingto claim 3, wherein R^(B) is —NHC(O)—R^(Q).
 5. A compound according toclaim 1, wherein R² is —C₅₋₆cycloalkyl-C₁₋₃alkyl.
 6. A compoundaccording to claim 1, wherein R⁴ is hydrogen.
 7. A compound, or apharmaceutically acceptable salt thereof, selected from the groupconsisting of:5-(3-methyl-4-(thiazole-4-carboxamido)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylic acid;5-(3-methoxy-4-(thiazole-4-carboxamido)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylicacid;5-(3-cyano-4-(thiazole-4-carboxamido)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylicacid;5-(3-ethyl-4-(thiazole-4-carboxamido)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylicacid;3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-(4-(thiazole-4-carboxamido)-3-(trifluoromethyl)phenyl)thiophene-2-carboxylicacid;3-(1-methyl-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(3-methyl-4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid;3-(1-(2-hydroxyethyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(3-methyl-4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid;3-(4-(4,4-difluorocyclohexyl)-1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid;3-(5-(2,4-dichlorophenyl)-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid; and3-(1-methyl-5-(p-tolyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid.
 8. A composition comprising a compound according to claims 1 andleast one pharmaceutically acceptable carrier or excipient.
 9. Acomposition comprising a compound according to claim 7 and at least onepharmaceutically acceptable carrier or excipient.
 10. A compound, or apharmaceutically acceptable salt thereof, selected from the groupconsisting of:5-(3-chloro-4-(thiazole-4-carboxamido)phenyl)-3-(1-methyl-5-(4-methylcyclohexyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylicacid;3-(1-(2-hydroxyethyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid;3-(1-(2,3-dihydroxypropyl)-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(4-(thiazole-4-carboxamido)phenyl)thiophene-2-carboxylicacid;5-(3-fluoro-4-(thiazole-4-carboxamido)phenyl)-3-(1-methyl-4-(4-methylcyclohexyl)-1,2,5,6-tetrahydropyridin-3-yl)thiophene-2-carboxylicacid; 3 -(5-cyclohexyl- 1-methyl- 1,2,3 ,6-tetrahydro-pyridin-4-yl)-5-{4- [(thiazole-4-carbonyl)-amino]-phenyl }-thiophene-2-carboxylic acid;and 3 -(4-cyclohexyl- 1-methyl- 1,2,5 ,6-tetrahydro-pyridin-3-yl)-5-{4-[(thiazole-4-carbonyl)-amino]-phenyl }-thiophene-2-carboxylicacid.